{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","name":"Adjacent Evidence Brief: Sulforaphane NRF2 — full paper","doi":"10.17605/OSF.IO/B42KF","doi_status":"minted","osf_url":"https://osf.io/b42kf/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_e4c9292fd6da4a72/chain","content_hash":"sha256:40dfc9e68b0bcdeb1513c586a5d6f1b21b6dbad1495ee9da74a807610f9ced84","provenance_passport":{"publication_id":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","submission_id":"c56ee3e3-d226-4e1e-93fd-6c8879f3c811","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:40dfc9e68b0bcdeb1513c586a5d6f1b21b6dbad1495ee9da74a807610f9ced84","persistent_identifiers":{"doi":"10.17605/OSF.IO/B42KF","osf_url":"https://osf.io/b42kf/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":{"recommendation":"unavailable","available":false,"checked_at":"2026-06-27T14:15:54.975312+00:00","reason":"integrity_unavailable: The read operation timed out","matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null,"status":"unavailable"},"provenance":{"dw_artifact_id":"claim_e4c9292fd6da4a72","dw_chain_url":"https://provenance.researka.org/artifacts/claim_e4c9292fd6da4a72/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","object_type":"publication","parent_object_id":"c56ee3e3-d226-4e1e-93fd-6c8879f3c811","title":"Adjacent Evidence Brief: Sulforaphane NRF2 — full paper","body_markdown":"# Adjacent Evidence Brief: Sulforaphane NRF2 — full paper\n## Abstract\n\nThis synthesis tests the thesis that evidence for Sulforaphane NRF2 is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.\n\nEvidence-honesty note: The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.\n\nThis paper synthesizes evidence on Sulforaphane NRF2 across 21 included source papers and 902 high-confidence extracted claims.\n\nThe evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, with 5 cross-study disagreements across the evidence base.\n\nPositive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, immune and inflammation, mechanism, and cardiometabolic outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that Sulforaphane NRF2 should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a Evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-sulforaphane_nrf2-v06-DAILY-2026-06-27T12-02-36Z`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-27.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `sulforaphane NRF2 AND aging AND human`\n- `sulforaphane NRF2 AND older adults`\n- `sulforaphane NRF2 AND randomized controlled trial`\n- `sulforaphane AND aging AND human`\n- `sulforaphane AND older adults`\n- `sulforaphane AND randomized controlled trial`\n- `NRF2 AND aging AND human`\n- `NRF2 AND older adults`\n- `NRF2 AND randomized controlled trial`\n- `broccoli sprout AND aging AND human`\n\n### Eligibility criteria\n- Sources whose primary content addresses sulforaphane nrf2.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 161 records in the receipt-candidate union, 60 were classified as source candidates and 21 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 161 |\n| Classified source candidates | 60 |\n| No extractable claims | 36 |\n| None-only claim binding | 7 |\n| Mixed partial-or-none claim-binding candidates | 41 |\n| Partial-only claim-binding candidates | 11 |\n| Strict high-confidence sources | 6 |\n| Admitted final sources | 21 |\n\n### Exclusion reasons\n- No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nRisk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, immune and inflammation, mechanism); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.\n\n## Results\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.\n\n| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Sulforaphane NRF2 / Contextual Adjacent Evidence | n=12; claims=441 | significant source statistic in 8/12 sources; receipt-level direction coded unclear | 11 indirect; 1 review | limited corpus depth in this outcome class |\n| Sulforaphane NRF2 / Immune and Inflammation | n=4; claims=103 | significant source statistic in 3/4 sources; receipt-level direction coded unclear | 2 indirect; 2 mechanistic | limited corpus depth in this outcome class |\n| Sulforaphane NRF2 / Mechanism | n=3; claims=160 | significant source statistic in 3/3 sources; receipt-level direction coded unclear | 3 mechanistic | limited corpus depth in this outcome class |\n| Sulforaphane NRF2 / Cardiometabolic | n=2; claims=198 | unclear signal in 1/2 sources | 2 indirect | limited corpus depth in this outcome class |\n\nThis evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.\n\n### Contextual Adjacent Evidence Outcomes\n\nIn animal/preclinical evidence, contextual Adjacent Evidence remains a separate Results slice for Sulforaphane NRF2 (n=12; claims=441; significant source statistic in 8/12 sources; receipt-level direction coded unclear; 11 indirect; 1 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:\n- Brown 2015 (Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways; representative statistic p = 0.01; source-level statistic reported; direction=mixed; directness=indirect; tier=B2).\n- Bose 2020 (Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling; representative statistic p = .0087; source-level statistic reported; direction=unclear; directness=indirect; tier=B2).\n- Lu 2024 (Sulforaphane attenuates phosgene-induced acute lung injury via the Nrf2-HO-1/NQO1 pathway; representative statistic P<0.05; source-level statistic reported; direction=positive; directness=indirect; tier=B2).\n- Padron 2022 (Stretch Causes Cell Stress and the Downregulation of Nrf2 in Primary Amnion Cells; representative statistic p < 0.05; source-level statistic reported; direction=unclear; directness=indirect; tier=B2).\n\nDirection reconciliation: receipt-level null or unclear coding is conservative claim-level coding. Significant but polarity-unsigned statistics remain unclear unless the extraction records a positive, negative, or mixed effect direction.\n\n### Immune and Inflammation Outcomes\n\nImmune and Inflammation remains a separate Results slice for Sulforaphane NRF2 (n=4; claims=103; significant source statistic in 3/4 sources; receipt-level direction coded unclear; 2 indirect; 2 mechanistic; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:\n- Subedi 2019 (Sulforaphane-Enriched Broccoli Sprouts Pretreated by Pulsed Electric Fields Reduces Neuroinflammation and Ameliorates; representative statistic P < 0.05; source-level statistic reported; direction=unclear; directness=mechanistic; tier=C1).\n- Duran 2016 (A proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation; representative statistic p = 0.001; source-level statistic reported; direction=unclear; directness=indirect; tier=B2).\n- Chen 2025 (Effects of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae based; representative statistic p < 0.05; source-level statistic reported; direction=null; directness=mechanistic; tier=C1).\n- Ruhee 2025 (Effects of Sulforaphane Treatment on Skeletal Muscle from Exhaustive Exercise-Induced Inflammation and Oxidative Stress; 8 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2).\n\n### Mechanism Outcomes\n\nMechanism remains a separate Results slice for Sulforaphane NRF2 (n=3; claims=160; significant source statistic in 3/3 sources; receipt-level direction coded unclear; 3 mechanistic; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:\n- Ahmadian 2026 (Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model; representative statistic p = 0.0009; source-level statistic reported; direction=unclear; directness=mechanistic; tier=C1).\n- He 2022 (The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and; representative statistic P < 0.05; source-level statistic reported; direction=unclear; directness=mechanistic; tier=C1).\n- Koduri 2026 (Oxidative Stress in Keratoconus Is Evident in Tear Fluid and Stromal Cells and Alleviated in Cell Culture by; representative statistic P ≤ 0.05; source-level statistic reported; direction=unclear; directness=mechanistic; tier=C1).\n\n### Cardiometabolic Outcomes\n\nIn animal/preclinical evidence, cardiometabolic remains a separate Results slice for Sulforaphane NRF2 (n=2; claims=198; unclear signal in 1/2 sources; 2 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:\n- Sharma 2026 (The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway; 155 extracted claim(s); receipt-level direction is the coded finding; direction=unclear; directness=indirect; tier=B2).\n- Xin 2018 (Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn; 43 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2).\n\n## Limitations\n\nThe principal limitation is evidence-role imbalance. The retained corpus contains no sources classified primarily as direct clinical evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, which means causal interpretation depends on how much weight is assigned to each evidence tier.\n\nA second limitation is endpoint heterogeneity. Study-level signals span the contextual adjacent evidence outcome class, the contextual adjacent evidence, immune and inflammation, cardiometabolic outcome classes, no dominant outcome class, and the contextual adjacent evidence outcome class; these domains cannot be pooled narratively without losing clinically relevant differences in measurement, population, and study design.\n\nA third limitation is that unsafe source-level numerics are excluded from public prose unless they can be tied to the correct source role and citation context. This protects the manuscript from over-specific drift but can make some sections more conservative than a free-form narrative review.\n\n## Conclusion\n\nFor Sulforaphane NRF2, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.\n\n## What This Synthesis Adds\n\nThis synthesis maps 21 included sources on Sulforaphane Nrf2 across 4 outcome classes and 5 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.\n\nAcross 21 curated reference papers, the evidence base for Sulforaphane Nrf2 shows a context-dependent profile. Positive signals appear in: contextual other. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Sulforaphane Nrf2 anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nIn animal/preclinical evidence, the strongest unresolved contrast is the null vs positive between Lu 2024 and Xie 2025 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.\n\nThis synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.\n\n### Boundary-Condition Matrix\n\n| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| cardiometabolic | 0 | 2 | null, unclear | direct interventional hard-endpoint gap |\n| contextual adjacent evidence | 0 | 12 | mixed, null, positive, unclear | conflict-resolution gap |\n| mechanism | 0 | 3 | unclear | direct interventional hard-endpoint gap |\n| immune and inflammation | 0 | 4 | null, unclear | direct interventional hard-endpoint gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null, unclear |\n| P2 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 12 indirect sources; direction profile: mixed, null, positive, unclear |\n| P3 | mechanism: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: unclear |\n| P4 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 4 indirect sources; direction profile: null, unclear |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Sulforaphane Nrf2 should target the **cardiometabolic** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.\n\n## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\n- In animal/preclinical evidence, Sharma 2026; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=unclear.\n- Brown 2015; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=mixed; representative statistic=P = 0.0005.\n- Bose 2020; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.0001.\n- Clifford 2021; tier=B2; directness=review; endpoint=contextual adjacent evidence; direction=null.\n- Lu 2024; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.001.\n- Xin 2018; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null.\n- Padron 2022; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.01.\n- Fu 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.517.\n- Duran 2016; tier=B2; directness=indirect; endpoint=immune inflammation; direction=unclear; representative statistic=P = 0.001.\n- Doss 2016; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P = 0.0082.\n\n### Source Classification Map\n\nEach retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.\n\n- In animal/preclinical evidence, Sharma 2026: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=155.\n- Brown 2015: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=mixed; claims=142.\n- Bose 2020: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=80.\n- Clifford 2021: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=46.\n- Lu 2024: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=positive; claims=45.\n- Xin 2018: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=43.\n- Padron 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=36.\n- Fu 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=31.\n- Duran 2016: outcome=immune inflammation; directness=indirect; tier=B2; direction=unclear; claims=27.\n- Doss 2016: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=19.\n- Wise 2016: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=14.\n- Mohammad 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=13.\n- Ruhee 2025: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=8.\n- OMealey 2016: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6.\n- Xie 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=5.\n- Mitra 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=4.\n- Ahmadian 2026: outcome=mechanism; directness=mechanistic; tier=C1; direction=unclear; claims=70.\n- He 2022: outcome=mechanism; directness=mechanistic; tier=C1; direction=unclear; claims=61.\n- Subedi 2019: outcome=immune inflammation; directness=mechanistic; tier=C1; direction=unclear; claims=46.\n- Koduri 2026: outcome=mechanism; directness=mechanistic; tier=C1; direction=unclear; claims=29.\n- Chen 2025: outcome=immune inflammation; directness=mechanistic; tier=C1; direction=null; claims=22.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Load-Bearing Tensions\n\n- Additional corpus sources included animal/preclinical evidence; severity 4 null vs positive: Lu 2024 vs Xie 2025; Lu 2024 (positive on contextual other) vs Xie 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Lu 2024 vs Fu 2026; Lu 2024 (positive on contextual other) vs Fu 2026 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Lu 2024 vs Wise 2016; Lu 2024 (positive on contextual other) vs Wise 2016 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Lu 2024 vs OMealey 2016; Lu 2024 (positive on contextual other) vs OMealey 2016 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Lu 2024 vs Clifford 2021; Lu 2024 (positive on contextual other) vs Clifford 2021 (null on contextual other) — partial conflict\n\n## References\n\n- **Sharma 2026.** _The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway._ Science Advances, 2026. DOI: 10.1126/sciadv.aed2478. PMID: 42234761.\n- **Brown 2015.** _Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways._ Respiratory Research, 2015. DOI: 10.1186/s12931-015-0253-z. PMID: 26369337.\n- **Bose 2020.** _Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling._ Aging Cell, 2020. DOI: 10.1111/acel.13261. PMID: 33067900.\n- **Ahmadian 2026.** _Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model._ Scientific Reports, 2026. DOI: 10.1038/s41598-026-40709-x. PMID: 41708791.\n- **He 2022.** _The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism._ Frontiers in Nutrition, 2022. DOI: 10.3389/fnut.2022.893344. PMID: 35832050.\n- **Subedi 2019.** _Sulforaphane-Enriched Broccoli Sprouts Pretreated by Pulsed Electric Fields Reduces Neuroinflammation and Ameliorates Scopolamine-Induced Amnesia in Mouse Brain through Its Antioxidant Ability via Nrf2-HO-1 Activation._ Oxidative Medicine and Cellular Longevity, 2019. DOI: 10.1155/2019/3549274. PMID: 31049133.\n- **Clifford 2021.** _The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials._ Molecular Biology Reports, 2021. DOI: 10.1007/s11033-020-06041-x. PMID: 33515348.\n- **Lu 2024.** _Sulforaphane attenuates phosgene-induced acute lung injury via the Nrf2-HO-1/NQO1 pathway._ Journal of Thoracic Disease, 2024. DOI: 10.21037/jtd-24-819. PMID: 39552873.\n- **Xin 2018.** _Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway._ Redox Biology, 2018. DOI: 10.1016/j.redox.2017.12.016. PMID: 29353218.\n- **Padron 2022.** _Stretch Causes Cell Stress and the Downregulation of Nrf2 in Primary Amnion Cells._ Biomolecules, 2022. DOI: 10.3390/biom12060766. PMID: 35740891.\n- **Fu 2026.** _Sulforaphane Alleviates Zearalenone-Induced Oxidative Stress in Bovine Mammary Epithelial Cells._ Animals : an Open Access Journal from MDPI, 2026. DOI: 10.3390/ani16111602. PMID: 42278036.\n- **Koduri 2026.** _Oxidative Stress in Keratoconus Is Evident in Tear Fluid and Stromal Cells and Alleviated in Cell Culture by Sulforaphane._ Investigative Ophthalmology & Visual Science, 2026. DOI: 10.1167/iovs.67.5.1. PMID: 42065481.\n- **Duran 2016.** _A proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation._ Respiratory Research, 2016. DOI: 10.1186/s12931-016-0406-8. PMID: 27450419.\n- **Chen 2025.** _Effects of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae based on the Nrf2/ARE signaling pathway._ Central-European Journal of Immunology, 2025. DOI: 10.5114/ceji.2025.152018. PMID: 41438358.\n- **Doss 2016.** _Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease._ PLoS ONE, 2016. DOI: 10.1371/journal.pone.0152895. PMID: 27071063.\n- **Wise 2016.** _Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial._ PLoS ONE, 2016. DOI: 10.1371/journal.pone.0163716. PMID: 27832073.\n- **Mohammad 2022.** _Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2._ Antioxidants, 2022. DOI: 10.3390/antiox11010156. PMID: 35052660.\n- **Ruhee 2025.** _Effects of Sulforaphane Treatment on Skeletal Muscle from Exhaustive Exercise-Induced Inflammation and Oxidative Stress Through the Nrf2/HO-1 Signaling Pathway._ Antioxidants, 2025. DOI: 10.3390/antiox14020210. PMID: 40002396.\n- **OMealey 2016.** _Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission._ Redox Biology, 2016. DOI: 10.1016/j.redox.2016.11.007. PMID: 27889639.\n- **Xie 2025.** _Sulforaphane alleviates hepatocyte pyroptosis via activating Nrf2-HO-1 signaling during septic acute liver injury._ Frontiers in Pharmacology, 2025. DOI: 10.3389/fphar.2025.1690067. PMID: 41181585.\n- **Mitra 2026.** _Effect of Glucoraphanin on the Abundance of Nrf2 Regulated Genes Within Circulating Small Extracellular Vesicles: A Pilot Dietary Intervention._ Molecular Nutrition & Food Research, 2026. DOI: 10.1002/mnfr.70397. PMID: 41603376.\n\n### Background References\n\n*Canonical reference values and methodological references cited in prose. 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The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, with 5 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, immune and inflammation, mechanism, and cardiometabolic outcome classes. 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Evidence-honesty note: The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on Sulforaphane NRF2 across 21 included source papers and 902 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, with 5 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, immune and inflammation, mechanism, and cardiometabolic outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"This synthesis tests the thesis that evidence for Sulforaphane NRF2 is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"Evidence-honesty note: The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"This paper synthesizes evidence on Sulforaphane NRF2 across 21 included source papers and 902 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, with 5 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, immune and inflammation, mechanism, and cardiometabolic outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"The conclusion is that Sulforaphane NRF2 should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"This manuscript is reported as a Evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-sulforaphane_nrf2-v06-DAILY-2026-06-27T12-02-36Z`.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","claim":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, immune and inflammation, mechanism); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"| Sulforaphane NRF2 / Contextual Adjacent Evidence | n=12; claims=441 | significant source statistic in 8/12 sources; receipt-level direction coded unclear | 11 indirect; 1 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"In animal/preclinical evidence, contextual Adjacent Evidence remains a separate Results slice for Sulforaphane NRF2 (n=12; claims=441; significant source statistic in 8/12 sources; receipt-level direction coded unclear; 11 indirect; 1 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"Direction reconciliation: receipt-level null or unclear coding is conservative claim-level coding. Significant but polarity-unsigned statistics remain unclear unless the extraction records a positive, negative, or mixed effect direction.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"Chen 2025 (Effects of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae based; representative statistic p < 0.05; source-level statistic reported; direction=null; directness=mechanistic; tier=C1).","citation_support":[{"source_id":"source_10","study":"Effects of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae based on the Nrf2/ARE signaling pathway","doi":"10.5114/ceji.2025.152018","url":"https://doi.org/10.5114/ceji.2025.152018","support_kind":"cited_as_match","cited_as":"Chen 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"mechanistic","excerpt":"INTRODUCTION: To explore the mechanism of action of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae (MP) based on the nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. MATERIAL AND METHODS: The lung index, dry/wet weight ratio, inflammatory factor levels in alveolar lavage fluid, serum contents of interferon-γ (IFN-γ) and immunoglobulin G (IgG), oxidative stress markers, peripheral blood levels of T-lymphocyte subsets, pathological changes, and Nrf2, HO-1, and NQO1 expression were assessed. RESULTS: Compared to the control group, the MP group exhibited elevated lung index, reduced lung dry/wet weight ratio, elevated tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 contents, reduced IL-10 levels, raised IFN-γ, IgG and peripheral blood CD8 + levels, reduced CD3 + and CD4 + levels, CD4 + /CD8 + ratio, and superoxide dismutase (SOD) and glutathione (GSH) activity, elevated malondialdehyde (MDA) contents, destruction of lung tissue structure, elevated pathological scores, and diminished Nrf2, HO-1, and NQO1 levels."}],"candidate_sources":[]},{"claim_id":"claim_20","claim":"Ruhee 2025 (Effects of Sulforaphane Treatment on Skeletal Muscle from Exhaustive Exercise-Induced Inflammation and Oxidative Stress; 8 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2).","citation_support":[{"source_id":"source_12","study":"Effects of Sulforaphane Treatment on Skeletal Muscle from Exhaustive Exercise-Induced Inflammation and Oxidative Stress Through the Nrf2/HO-1 Signaling Pathway","doi":"10.3390/antiox14020210","url":"https://doi.org/10.3390/antiox14020210","support_kind":"cited_as_match","cited_as":"Ruhee 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Skeletal muscle is primarily involved in exercise performance and health promotion. Sulforaphane (SFN) is a naturally occurring isothiocyanate that indirectly activates the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), thus inducing the expression of Nrf2 target genes, including antioxidant enzymes. This study aimed to identify the effects of a single dose of SFN administration on exhaustive exercise-induced inflammation and oxidative stress in skeletal muscle tissue and elucidate the underlying mechanisms. Thirty-six mice were divided into four groups: control, SFN, exercise (Ex), and SFN + Ex. The SFN group and SFN + Ex group received SFN orally (50 mg/kg body weight) 2 h before the running test. Exercise significantly reduced plasma glucose levels, while the SFN-treated group exhibited a smaller reduction. Acute exhaustive exercise increased the expression of pro-inflammatory cytokines in muscle tissue, while the SFN + Ex group exhibited significantly reduced expression of pro-inflammatory cytokines."}],"candidate_sources":[]},{"claim_id":"claim_21","claim":"In animal/preclinical evidence, cardiometabolic remains a separate Results slice for Sulforaphane NRF2 (n=2; claims=198; unclear signal in 1/2 sources; 2 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"Xin 2018 (Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn; 43 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2).","citation_support":[{"source_id":"source_17","study":"Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway","doi":"10.1016/j.redox.2017.12.016","url":"https://doi.org/10.1016/j.redox.2017.12.016","support_kind":"cited_as_match","cited_as":"Xin 2018","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"AIMS: Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by sulforaphane (SFN) protects from, and deletion of the Nrf2 gene exaggerates, diabetic cardiomyopathy. Angiotensin II (Ang II) plays a critical role in the development of diabetic cardiomyopathy. Therefore, whether SFN prevents Ang II-induced cardiomyopathy through activation of Nrf2 was examined using wild-type, global deletion of Nrf2 gene (Nrf2-KO) and cardiomyocyte-specific overexpression of Nrf2 gene (Nrf2-TG) mice. METHODS AND RESULTS: Administration of a subpressor dose of Ang II to wild-type mice induced cardiac oxidative stress, inflammation, remodeling and dysfunction, all of which could be prevented by SFN treatment with Nrf2 up-regulation and activation. Nrf2-KO mice are susceptible, and Nrf2-TG mice are resistant, respectively, to Ang II-induced cardiomyopathy. Meanwhile, the ability of SFN to protect against Ang II-induced cardiac damage was lost in Nrf2-KO mice. Up-regulation and activation of Nrf2 by SFN is accompanied by activation of Akt, inhibition of glycogen synthase kinase (GSK)-3β, and accumulation of Fyn in nuclei."}],"candidate_sources":[]},{"claim_id":"claim_23","claim":"The principal limitation is evidence-role imbalance. The retained corpus contains no sources classified primarily as direct clinical evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, which means causal interpretation depends on how much weight is assigned to each evidence tier.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"A second limitation is endpoint heterogeneity. Study-level signals span the contextual adjacent evidence outcome class, the contextual adjacent evidence, immune and inflammation, cardiometabolic outcome classes, no dominant outcome class, and the contextual adjacent evidence outcome class; these domains cannot be pooled narratively without losing clinically relevant differences in measurement, population, and study design.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","claim":"For Sulforaphane NRF2, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_26","claim":"This synthesis maps 21 included sources on Sulforaphane Nrf2 across 4 outcome classes and 5 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_27","claim":"Across 21 curated reference papers, the evidence base for Sulforaphane Nrf2 shows a context-dependent profile. Positive signals appear in: contextual other. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Sulforaphane Nrf2 anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_28","claim":"In animal/preclinical evidence, the strongest unresolved contrast is the null vs positive between Lu 2024 and Xie 2025 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_29","claim":"This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_30","claim":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |","citation_support":[],"candidate_sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans.","source_id":"source_5","support_kind":"candidate_source_row"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","content_hash":"sha256:40dfc9e68b0bcdeb1513c586a5d6f1b21b6dbad1495ee9da74a807610f9ced84","nodes":[{"id":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","type":"publication","title":"Adjacent Evidence Brief: Sulforaphane NRF2 — full paper"},{"id":"claim_1","type":"claim","text":"This synthesis tests the thesis that evidence for Sulforaphane NRF2 is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. Evidence-honesty note: The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on Sulforaphane NRF2 across 21 included source papers and 902 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, with 5 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, immune and inflammation, mechanism, and cardiometabolic outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_2","type":"claim","text":"This synthesis tests the thesis that evidence for Sulforaphane NRF2 is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation."},{"id":"claim_3","type":"claim","text":"Evidence-honesty note: The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims."},{"id":"claim_4","type":"claim","text":"This paper synthesizes evidence on Sulforaphane NRF2 across 21 included source papers and 902 high-confidence extracted claims."},{"id":"claim_5","type":"claim","text":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, with 5 cross-study disagreements across the evidence base."},{"id":"claim_6","type":"claim","text":"Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, immune and inflammation, mechanism, and cardiometabolic outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_7","type":"claim","text":"The conclusion is that Sulforaphane NRF2 should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_8","type":"claim","text":"This manuscript is reported as a Evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-sulforaphane_nrf2-v06-DAILY-2026-06-27T12-02-36Z`."},{"id":"claim_9","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text."},{"id":"claim_10","type":"claim","text":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification."},{"id":"claim_11","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, immune and inflammation, mechanism); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_12","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_13","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim."},{"id":"claim_14","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_15","type":"claim","text":"| Sulforaphane NRF2 / Contextual Adjacent Evidence | n=12; claims=441 | significant source statistic in 8/12 sources; receipt-level direction coded unclear | 11 indirect; 1 review | limited corpus depth in this outcome class |"},{"id":"claim_16","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_17","type":"claim","text":"In animal/preclinical evidence, contextual Adjacent Evidence remains a separate Results slice for Sulforaphane NRF2 (n=12; claims=441; significant source statistic in 8/12 sources; receipt-level direction coded unclear; 11 indirect; 1 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:"},{"id":"claim_18","type":"claim","text":"Direction reconciliation: receipt-level null or unclear coding is conservative claim-level coding. Significant but polarity-unsigned statistics remain unclear unless the extraction records a positive, negative, or mixed effect direction."},{"id":"claim_19","type":"claim","text":"Chen 2025 (Effects of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae based; representative statistic p < 0.05; source-level statistic reported; direction=null; directness=mechanistic; tier=C1)."},{"id":"claim_20","type":"claim","text":"Ruhee 2025 (Effects of Sulforaphane Treatment on Skeletal Muscle from Exhaustive Exercise-Induced Inflammation and Oxidative Stress; 8 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2)."},{"id":"claim_21","type":"claim","text":"In animal/preclinical evidence, cardiometabolic remains a separate Results slice for Sulforaphane NRF2 (n=2; claims=198; unclear signal in 1/2 sources; 2 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:"},{"id":"claim_22","type":"claim","text":"Xin 2018 (Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn; 43 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2)."},{"id":"claim_23","type":"claim","text":"The principal limitation is evidence-role imbalance. The retained corpus contains no sources classified primarily as direct clinical evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, which means causal interpretation depends on how much weight is assigned to each evidence tier."},{"id":"claim_24","type":"claim","text":"A second limitation is endpoint heterogeneity. Study-level signals span the contextual adjacent evidence outcome class, the contextual adjacent evidence, immune and inflammation, cardiometabolic outcome classes, no dominant outcome class, and the contextual adjacent evidence outcome class; these domains cannot be pooled narratively without losing clinically relevant differences in measurement, population, and study design."},{"id":"claim_25","type":"claim","text":"For Sulforaphane NRF2, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."},{"id":"claim_26","type":"claim","text":"This synthesis maps 21 included sources on Sulforaphane Nrf2 across 4 outcome classes and 5 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit."},{"id":"claim_27","type":"claim","text":"Across 21 curated reference papers, the evidence base for Sulforaphane Nrf2 shows a context-dependent profile. Positive signals appear in: contextual other. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Sulforaphane Nrf2 anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established."},{"id":"claim_28","type":"claim","text":"In animal/preclinical evidence, the strongest unresolved contrast is the null vs positive between Lu 2024 and Xie 2025 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over."},{"id":"claim_29","type":"claim","text":"This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary."},{"id":"claim_30","type":"claim","text":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |"},{"id":"source_1","type":"source","study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","year":2026,"doi":"10.1126/sciadv.aed2478","url":"https://doi.org/10.1126/sciadv.aed2478","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sharma 2026","excerpt":"The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration."},{"id":"source_2","type":"source","study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling","year":2020,"doi":"10.1111/acel.13261","url":"https://doi.org/10.1111/acel.13261","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bose 2020","excerpt":"Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group."},{"id":"source_3","type":"source","study":"Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model","year":2026,"doi":"10.1038/s41598-026-40709-x","url":"https://doi.org/10.1038/s41598-026-40709-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Ahmadian 2026","excerpt":"Azoospermia, the complete absence of sperm in the ejaculate, presents a major barrier to male fertility. Oxidative stress and impaired cellular homeostasis are key contributors to germ cell loss, particularly in chemotherapy-induced azoospermia. Sulforaphane (SFN), a potent activator of the Nrf2 pathway, offers antioxidant benefits, but its systemic delivery is limited by bioavailability and potential reductive stress. This study aimed to evaluate the regenerative potential of SFN-loaded exosomes (SFN + EXO) in a rat model of azoospermia. Human serum-derived exosomes were isolated, characterized and engineered to encapsulate SFN. Azoospermia was induced in Wistar rats via intratesticular busulfan injection. Animals were assigned to five groups: healthy control, azoospermic control, SFN, exosomes (EXO) and SFN + EXO. Spermatogenesis parameters, histopathology, testosterone levels, oxidative stress markers and gene expression of Nrf2, autophagy and germ cell markers were evaluated. SFN + EXO treatment significantly improved sperm count, motility, morphology and testis weight index compared to controls and monotherapy groups."},{"id":"source_4","type":"source","study":"The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism","year":2022,"doi":"10.3389/fnut.2022.893344","url":"https://doi.org/10.3389/fnut.2022.893344","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"He 2022","excerpt":"Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables such as broccoli and brussels sprouts, has a variety of biological functions. This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate the underlying mechanisms. UC was induced in mice with administration of 2% DSS in drinking water for 7 days. Male C57BL/6 mice were treated with Mesalazine (50 and 100 mg/kg body weight) and various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index (DAI) scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment. SFN also partially restored the perturbed gut microbiota composition and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration."},{"id":"source_5","type":"source","study":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials","year":2021,"doi":"10.1007/s11033-020-06041-x","url":"https://doi.org/10.1007/s11033-020-06041-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Clifford 2021","excerpt":"We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans."},{"id":"source_6","type":"source","study":"Sulforaphane attenuates phosgene-induced acute lung injury via the Nrf2-HO-1/NQO1 pathway","year":2024,"doi":"10.21037/jtd-24-819","url":"https://doi.org/10.21037/jtd-24-819","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Lu 2024","excerpt":"BACKGROUND: Sulforaphane (SFN) has been demonstrated to exert a protective role in various diseases. However, the role of SFN in phosgene-induced acute lung injury (P-ALI) remains unclear. This study aimed to explore the role and mechanism of SFN in P-ALI and provide a theoretical basis for the clinical prevention and treatment of P-ALI. METHODS: A mouse model of P-ALI was established followed by phosgene gas inhalation at a dose of 4.17 g/m 3 for 5 min. The survival rate, lung coefficient and hematoxylin and eosin (H&E) staining, lung pathology scoring, and bronchoalveolar lavage fluid (BALF) analysis were performed to evaluate lung tissue damage. The real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis were utilized to evaluate the relative expression levels of inflammation factors and protein expression. RESULTS: Compared with the control group, destruction of alveolar structure, pulmonary edema, lung tissue inflammation and oxidative stress occurred after phosgene exposure."},{"id":"source_7","type":"source","study":"Stretch Causes Cell Stress and the Downregulation of Nrf2 in Primary Amnion Cells","year":2022,"doi":"10.3390/biom12060766","url":"https://doi.org/10.3390/biom12060766","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Padron 2022","excerpt":"Nuclear-factor-E2-related factor 2 (Nrf2) is a key transcription factor for the regulation of cellular responses to cellular stress and inflammation, and its expression is significantly lower after spontaneous term labor in human fetal membranes. Pathological induction of inflammation can lead to adverse pregnancy outcomes such as pre-eclampsia, preterm labor, and fetal death. As stretch forces are known to act upon the fetal membranes in utero, we aimed to ascertain the effect of stretch on Nrf2 to increase our understanding of the role of this stimulus on cells of the amnion at term. Our results indicated a significant reduction in Nrf2 expression in stretched isolated human amnion epithelial cells (hAECs) that could be rescued with sulforaphane treatment. Downregulation of Nrf2 as a result of stretch was accompanied with activation of proinflammatory nuclear factor-kB (NF-kB) and increases in LDH activity, ROS, and HMGB1. This work supports stretch as a key modulator of cellular stress and inflammation in the fetal membranes."},{"id":"source_8","type":"source","study":"Sulforaphane Alleviates Zearalenone-Induced Oxidative Stress in Bovine Mammary Epithelial Cells","year":2026,"doi":"10.3390/ani16111602","url":"https://doi.org/10.3390/ani16111602","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Fu 2026","excerpt":"Zearalenone (ZEA) is a common contaminant in crops and animal feed. However, research on the effects of ZEA on animal mammary tissue is relatively limited. Sulforaphane (SFN) is a naturally active compound mainly derived from cruciferous vegetables (such as broccoli), with significant antioxidant and cytoprotective effects. The purpose of this study is the effect of SFN on ZEA-induced toxicity in bovine mammary epithelial cells (MAC-T). By treating MAC-T cells with different concentrations of ZEA and SFN for 24 h, the results showed that different concentrations of ZEA (10, 20, 40, 60, 80, or 100 μM) could inhibit MAC-T cell viability. Treatment with SFN at concentrations of 1, 2.5, and 5 μM had no significant effect on cell viability. The results of combined treatment with 10 μM ZEA and 1, 2.5, or 5 μM SFN showed that SFN could significantly reverse the decrease in cell viability caused by ZEA; reduce the increase in lactate dehydrogenase (LDH) release, reactive oxygen species (ROS), and malondialdehyde (MDA) content induced by ZEA; and increase the levels of glutathione (GSH), superoxide dismutase (SOD), and mitochondrial membrane potential that were decreased by ZEA."},{"id":"source_9","type":"source","study":"Oxidative Stress in Keratoconus Is Evident in Tear Fluid and Stromal Cells and Alleviated in Cell Culture by Sulforaphane","year":2026,"doi":"10.1167/iovs.67.5.1","url":"https://doi.org/10.1167/iovs.67.5.1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Koduri 2026","excerpt":"PURPOSE: Keratoconus (KC) is a common eye disease characterized by progressive corneal thinning and steepening. Despite multiple treatment options, there is no definitive cure for KC. Previously we identified loss and dysregulation of nuclear factor erythroid 2-related factor 2 (NRF2) mediated antioxidant functions in stromal cells and extracellular matrix (ECM) in KC. Here we used tear fluid samples and cell culture models to investigate oxidative stress in KC. METHODS: Primary human KC and donor (DN) stromal fibroblasts were exposed to hydrogen peroxide (H2O2) to induce oxidative stress and treated with sulforaphane (SFN) for antioxidant rescue. The fibroblasts were then assessed for NRF2 activation and apoptosis by measuring TXNRD1, HMOX1, NRF2, and GPX3 expression and caspase-3/7 activity. ML385 was used to inhibit NRF2 functions in DN fibroblast cultures followed by measurements of cell death (Caspase 3/7), proliferation (BrdU and Ki-67 labeling) and ECM deposition by immunohistology. Oxidative stress was directly assessed in KC and non-KC subjects by measuring malondialdehyde (MDA) and glutathione peroxidase 3 (GPX3) levels in the tear fluid."},{"id":"source_10","type":"source","study":"Effects of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae based on the Nrf2/ARE signaling pathway","year":2025,"doi":"10.5114/ceji.2025.152018","url":"https://doi.org/10.5114/ceji.2025.152018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Chen 2025","excerpt":"INTRODUCTION: To explore the mechanism of action of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae (MP) based on the nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. MATERIAL AND METHODS: The lung index, dry/wet weight ratio, inflammatory factor levels in alveolar lavage fluid, serum contents of interferon-γ (IFN-γ) and immunoglobulin G (IgG), oxidative stress markers, peripheral blood levels of T-lymphocyte subsets, pathological changes, and Nrf2, HO-1, and NQO1 expression were assessed. RESULTS: Compared to the control group, the MP group exhibited elevated lung index, reduced lung dry/wet weight ratio, elevated tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 contents, reduced IL-10 levels, raised IFN-γ, IgG and peripheral blood CD8 + levels, reduced CD3 + and CD4 + levels, CD4 + /CD8 + ratio, and superoxide dismutase (SOD) and glutathione (GSH) activity, elevated malondialdehyde (MDA) contents, destruction of lung tissue structure, elevated pathological scores, and diminished Nrf2, HO-1, and NQO1 levels."},{"id":"source_11","type":"source","study":"Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2","year":2022,"doi":"10.3390/antiox11010156","url":"https://doi.org/10.3390/antiox11010156","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Mohammad 2022","excerpt":"Age is one of the major risk factors for the development of chronic pathologies, including kidney diseases. Oxidative stress and mitochondrial dysfunction play a pathogenic role in aging kidney disease. Transcription factor NRF2, a master regulator of redox homeostasis, is altered during aging, but the exact implications of altered NRF2 signaling on age-related renal mitochondrial impairment are not yet clear. Herein, we investigated the role of sulforaphane, a well-known NRF2 activator, on age-related mitochondrial and kidney dysfunction. Young (2-4 month) and aged (20-24 month) male Fischer 344 rats were treated with sulforaphane (15 mg/kg body wt/day) in drinking water for four weeks. We observed significant impairment in renal cortical mitochondrial function along with perturbed redox homeostasis, decreased kidney function and marked impairment in NRF2 signaling in aged Fischer 344 rats. Sulforaphane significantly improved mitochondrial function and ameliorated kidney injury by increasing cortical NRF2 expression and activity and decreasing protein expression of KEAP1, an NRF2 repressor."},{"id":"source_12","type":"source","study":"Effects of Sulforaphane Treatment on Skeletal Muscle from Exhaustive Exercise-Induced Inflammation and Oxidative Stress Through the Nrf2/HO-1 Signaling Pathway","year":2025,"doi":"10.3390/antiox14020210","url":"https://doi.org/10.3390/antiox14020210","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Ruhee 2025","excerpt":"Skeletal muscle is primarily involved in exercise performance and health promotion. Sulforaphane (SFN) is a naturally occurring isothiocyanate that indirectly activates the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), thus inducing the expression of Nrf2 target genes, including antioxidant enzymes. This study aimed to identify the effects of a single dose of SFN administration on exhaustive exercise-induced inflammation and oxidative stress in skeletal muscle tissue and elucidate the underlying mechanisms. Thirty-six mice were divided into four groups: control, SFN, exercise (Ex), and SFN + Ex. The SFN group and SFN + Ex group received SFN orally (50 mg/kg body weight) 2 h before the running test. Exercise significantly reduced plasma glucose levels, while the SFN-treated group exhibited a smaller reduction. Acute exhaustive exercise increased the expression of pro-inflammatory cytokines in muscle tissue, while the SFN + Ex group exhibited significantly reduced expression of pro-inflammatory cytokines."},{"id":"source_13","type":"source","study":"Sulforaphane alleviates hepatocyte pyroptosis via activating Nrf2-HO-1 signaling during septic acute liver injury","year":2025,"doi":"10.3389/fphar.2025.1690067","url":"https://doi.org/10.3389/fphar.2025.1690067","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Xie 2025","excerpt":"OBJECTIVE: Acute liver injury (ALI) caused by sepsis is a fatal disease with a high mortality rate and poor prognosis. Sulforaphane (SFN) is a natural isothiocyanate that has robust antioxidant and anti-inflammatory properties. The aim of this study was to identify the pharmacological effects and therapeutic mechanisms of SFN in lipopolysaccharide (LPS)-induced ALI. METHODS: The role of SFN in ALI was investigated using a mouse model of LPS-induced ALI. Briefly, eighteen mice were divided into three groups: control, LPS, and LPS + SFN, which were intraperitoneally injected for 2 days before LPS treatment. 24 h after the LPS injection, blood and liver tissues were collected for further analysis. RESULTS: The hematoxylin and eosin (HE) staining showed a lot of visible necrosis areas, inflammatory cell infiltration, and congestion in liver. Meanwhile, Ly6G and F4/80 staining showed increased infiltration of neutrophils and macrophages in liver, these results indicated that LPS induced sever ALI. As inflammatory response plays a vital role in the pathogenesis of LPS-induced ALI, we detected the occurrence of pyroptosis in liver by ribonucleic acid (RNA) sequencing."},{"id":"source_14","type":"source","study":"Effect of Glucoraphanin on the Abundance of Nrf2 Regulated Genes Within Circulating Small Extracellular Vesicles: A Pilot Dietary Intervention","year":2026,"doi":"10.1002/mnfr.70397","url":"https://doi.org/10.1002/mnfr.70397","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Mitra 2026","excerpt":"Cruciferous vegetables, including broccoli, are associated with a reduced risk of age-related chronic diseases. Broccoli accumulates glucoraphanin, which is hydrolyzed to sulforaphane, an isothiocyanate, that activates antioxidant genes via nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor, thereby alleviating age-related diseases. However, sulforaphane's rapid metabolism and excretion raise questions about its efficacy on peripheral tissues. We hypothesize that consumption of a glucoraphanin-rich broccoli soup induces small extracellular vesicles (sEVs) in the systemic circulation, containing Nrf2-induced antioxidant genes, mediating the effects of broccoli consumption on peripheral tissues. Nine adults participated in a two-arm, single-blinded, randomized crossover trial and consumed a glucoraphanin-rich broccoli soup (intervention) and a control soup. Plasma samples were analyzed to quantify abundance of Nrf2 regulated genes within circulating sEVs, while urine samples were analyzed to determine sulforaphane pharmacokinetics. While sulforaphane was detected in urine following the intervention (p < 0."},{"id":"source_15","type":"source","study":"Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways","year":2015,"doi":"10.1186/s12931-015-0253-z","url":"https://doi.org/10.1186/s12931-015-0253-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Brown 2015","excerpt":"BACKGROUND: It is widely recognized that deep inspiration (DI), either before methacholine (MCh) challenge (Bronchoprotection, BP) or after MCh challenge (Bronchodilation, BD) protects against this challenge in healthy individuals, but not in asthmatics. Sulforaphane, a dietary antioxidant and antiinflammatory phytochemical derived from broccoli, may affect the pulmonary bronchoconstrictor responses to MCh and the responses to DI in asthmatic patients. METHODS: Forty-five moderate asthmatics were administered sulforaphane (100 μmol daily for 14 days), BP, BD, lung volumes by body-plethsmography, and airway morphology by computed tomography (CT) were measured pre- and post sulforaphane consumption. RESULTS: Sulforaphane ameliorated the bronchoconstrictor effects of MCh on FEV1 significantly (on average by 21 %; p = 0.01) in 60 % of these asthmatics. Interestingly, in 20 % of the asthmatics, sulforaphane aggravated the bronchoconstrictor effects of MCh and in a similar number was without effect, documenting the great heterogeneity of the responsiveness of these individuals to sulforaphane."},{"id":"source_16","type":"source","study":"Sulforaphane-Enriched Broccoli Sprouts Pretreated by Pulsed Electric Fields Reduces Neuroinflammation and Ameliorates Scopolamine-Induced Amnesia in Mouse Brain through Its Antioxidant Ability via Nrf2-HO-1 Activation","year":2019,"doi":"10.1155/2019/3549274","url":"https://doi.org/10.1155/2019/3549274","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Subedi 2019","excerpt":"Activated microglia-mediated neuroinflammation plays a key pathogenic role in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemia. Sulforaphane is an active compound produced after conversion of glucoraphanin by the myrosinase enzyme in broccoli ( Brassica oleracea var) sprouts. Dietary broccoli extract as well as sulforaphane has previously known to mitigate inflammatory conditions in aged models involving microglial activation. Here, we produced sulforaphane-enriched broccoli sprouts through the pretreatment of pulsed electric fields in order to trigger the biological role of normal broccoli against lipopolysaccharide-activated microglia. The sulforaphane-enriched broccoli sprouts showed excellent potency against neuroinflammation conditions, as evidenced by its protective effects in both 6 and 24 h of microglial activation in vitro . We further postulated the underlying mechanism of action of sulforaphane in broccoli sprouts, which was the inhibition of an inflammatory cascade via the downregulation of mitogen-activated protein kinase (MAPK) signaling."},{"id":"source_17","type":"source","study":"Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway","year":2018,"doi":"10.1016/j.redox.2017.12.016","url":"https://doi.org/10.1016/j.redox.2017.12.016","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Xin 2018","excerpt":"AIMS: Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by sulforaphane (SFN) protects from, and deletion of the Nrf2 gene exaggerates, diabetic cardiomyopathy. Angiotensin II (Ang II) plays a critical role in the development of diabetic cardiomyopathy. Therefore, whether SFN prevents Ang II-induced cardiomyopathy through activation of Nrf2 was examined using wild-type, global deletion of Nrf2 gene (Nrf2-KO) and cardiomyocyte-specific overexpression of Nrf2 gene (Nrf2-TG) mice. METHODS AND RESULTS: Administration of a subpressor dose of Ang II to wild-type mice induced cardiac oxidative stress, inflammation, remodeling and dysfunction, all of which could be prevented by SFN treatment with Nrf2 up-regulation and activation. Nrf2-KO mice are susceptible, and Nrf2-TG mice are resistant, respectively, to Ang II-induced cardiomyopathy. Meanwhile, the ability of SFN to protect against Ang II-induced cardiac damage was lost in Nrf2-KO mice. Up-regulation and activation of Nrf2 by SFN is accompanied by activation of Akt, inhibition of glycogen synthase kinase (GSK)-3β, and accumulation of Fyn in nuclei."},{"id":"source_18","type":"source","study":"A proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation","year":2016,"doi":"10.1186/s12931-016-0406-8","url":"https://doi.org/10.1186/s12931-016-0406-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Duran 2016","excerpt":"UNLABELLED: Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, is implicated as a possible therapy for airway inflammation via induction of the transcription factor NF-E2-related factor 2 (NRF2). In this proof-of-concept clinical study, we show that supplementation of SFN with broccoli sprout homogenate in healthy human subjects did not induce expression of antioxidant genes or protect against neutrophilic airway inflammation in an ozone-exposure model. Therefore, dietary sulforaphane supplementation is not a promising candidate for larger scale clinical trials targeting airway inflammation. TRIAL REGISTRATION: NCT01625130 . Registered 19 June, 2012."},{"id":"source_19","type":"source","study":"Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease","year":2016,"doi":"10.1371/journal.pone.0152895","url":"https://doi.org/10.1371/journal.pone.0152895","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Doss 2016","excerpt":"Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. Our previous results indicate that the reduced oxidative stress capacity of sickle erythrocytes may be caused by decreased expression of NRF2 (Nuclear factor (erythroid-derived 2)-like 2), an oxidative stress regulator. We found that activation of NRF2 with sulforaphane (SFN) in erythroid progenitors significantly increased the expression of NRF2 targets HMOX1, NQO1, and HBG1 (subunit of fetal hemoglobin) in a dose-dependent manner. Therefore, we hypothesized that NRF2 activation with SFN may offer therapeutic benefits for SCD patients by restoring oxidative capacity and increasing fetal hemoglobin concentration. To test this hypothesis, we performed a Phase 1, open-label, dose-escalation study of SFN, contained in a broccoli sprout homogenate (BSH) that naturally contains SFN, in adults with SCD. The primary and secondary study endpoints were safety and physiological response to NRF2 activation, respectively. We found that BSH was well tolerated, and the few adverse events that occurred during the trial were not likely related to BSH consumption."},{"id":"source_20","type":"source","study":"Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial","year":2016,"doi":"10.1371/journal.pone.0163716","url":"https://doi.org/10.1371/journal.pone.0163716","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Wise 2016","excerpt":"BACKGROUND: COPD patients have high pulmonary and systemic oxidative stress that correlates with severity of disease. Sulforaphane has been shown to induce expression of antioxidant genes via activation of a transcription factor, nuclear factor erythroid-2 related factor 2 (Nrf2). METHODS: This parallel, placebo-controlled, phase 2, randomized trial was conducted at three US academic medical centers. Patients who met GOLD criteria for COPD and were able to tolerate bronchoscopies were randomly assigned (1:1:1) to receive placebo, 25 μmoles, or 150 μmoles sulforaphane daily by mouth for four weeks. The primary outcomes were changes in Nrf2 target gene expression (NQ01, HO1, AKR1C1 and AKR1C3) in alveolar macrophages and bronchial epithelial cells. Secondary outcomes included measures of oxidative stress and airway inflammation, and pulmonary function tests. RESULTS: Between July 2011 and May 2013, 89 patients were enrolled and randomized. Sulforaphane was absorbed in the patients as evident from their plasma metabolite levels. Changes in Nrf2 target gene expression relative to baseline ranged from 0.79 to 1."},{"id":"source_21","type":"source","study":"Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission","year":2016,"doi":"10.1016/j.redox.2016.11.007","url":"https://doi.org/10.1016/j.redox.2016.11.007","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"OMealey 2016","excerpt":"The KEAP1-Nrf2-ARE antioxidant system is a principal means by which cells respond to oxidative and xenobiotic stresses. Sulforaphane (SFN), an electrophilic isothiocyanate derived from cruciferous vegetables, activates the KEAP1-Nrf2-ARE pathway and has become a molecule-of-interest in the treatment of diseases in which chronic oxidative stress plays a major etiological role. We demonstrate here that the mitochondria of cultured, human retinal pigment epithelial (RPE-1) cells treated with SFN undergo hyperfusion that is independent of both Nrf2 and its cytoplasmic inhibitor KEAP1. Mitochondrial fusion has been reported to be cytoprotective by inhibiting pore formation in mitochondria during apoptosis, and consistent with this, we show Nrf2-independent, cytoprotection of SFN-treated cells exposed to the apoptosis-inducer, staurosporine. Mechanistically, SFN mitigates the recruitment and/or retention of the soluble fission factor Drp1 to mitochondria and to peroxisomes but does not affect overall Drp1 abundance."}],"edges":[{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_1","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_2","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_3","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_4","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_5","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_6","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_7","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_8","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_9","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_10","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_11","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_12","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_13","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_14","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_15","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_16","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_17","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_18","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_19","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_20","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_21","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_22","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_23","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_24","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_25","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_26","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_27","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_28","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_29","type":"contains_claim"},{"from":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","to":"claim_30","type":"contains_claim"}],"screening":{"identified":21,"screened":21,"excluded":0,"included":21,"included_or_retained":21,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"21 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","screening":{"identified":21,"screened":21,"excluded":0,"included":21,"included_or_retained":21,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"21 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["This synthesis tests the thesis that evidence for Sulforaphane NRF2 is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. Evidence-honesty note: The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on Sulforaphane NRF2 across 21 included source papers and 902 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 16 adjacent clinical sources, and 5 mechanistic or model-system sources, with 5 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, immune and inflammation, mechanism, and cardiometabolic outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, immune and inflammation, mechanism, and cardiometabolic outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","The conclusion is that Sulforaphane NRF2 should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","Direction reconciliation: receipt-level null or unclear coding is conservative claim-level coding. Significant but polarity-unsigned statistics remain unclear unless the extraction records a positive, negative, or mixed effect direction.","For Sulforaphane NRF2, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","Across 21 curated reference papers, the evidence base for Sulforaphane Nrf2 shows a context-dependent profile. Positive signals appear in: contextual other. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Sulforaphane Nrf2 anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nThe skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nSulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nTargeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,mechanistic\r\nThe Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,mechanistic\r\nThe effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review\r\nSulforaphane attenuates phosgene-induced acute lung injury via the Nrf2-HO-1/NQO1 pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nStretch Causes Cell Stress and the Downregulation of Nrf2 in Primary Amnion Cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nSulforaphane Alleviates Zearalenone-Induced Oxidative Stress in Bovine Mammary Epithelial Cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nOxidative Stress in Keratoconus Is Evident in Tear Fluid and Stromal Cells and Alleviated in Cell Culture by Sulforaphane,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,mechanistic\r\nEffects of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae based on the Nrf2/ARE signaling pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,mechanistic\r\nAge-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nEffects of Sulforaphane Treatment on Skeletal Muscle from Exhaustive Exercise-Induced Inflammation and Oxidative Stress Through the Nrf2/HO-1 Signaling Pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nSulforaphane alleviates hepatocyte pyroptosis via activating Nrf2-HO-1 signaling during septic acute liver injury,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nEffect of Glucoraphanin on the Abundance of Nrf2 Regulated Genes Within Circulating Small Extracellular Vesicles: A Pilot Dietary Intervention,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nSulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nSulforaphane-Enriched Broccoli Sprouts Pretreated by Pulsed Electric Fields Reduces Neuroinflammation and Ameliorates Scopolamine-Induced Amnesia in Mouse Brain through Its Antioxidant Ability via Nrf2-HO-1 Activation,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,mechanistic\r\nSulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nA proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nPhase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\n\"Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nSulforaphane is a Nrf2-independent inhibitor of mitochondrial fission,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"c67a74c0-4be2-4dfe-9638-ee889fd68d14","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway","doi":"10.1126/sciadv.aed2478","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 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pathway","doi":"10.21037/jtd-24-819","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Stretch Causes Cell Stress and the Downregulation of Nrf2 in Primary Amnion Cells","doi":"10.3390/biom12060766","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Sulforaphane Alleviates Zearalenone-Induced Oxidative Stress in Bovine Mammary Epithelial Cells","doi":"10.3390/ani16111602","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Oxidative Stress in Keratoconus Is Evident in Tear Fluid and Stromal Cells and Alleviated in Cell Culture by Sulforaphane","doi":"10.1167/iovs.67.5.1","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic"},{"study":"Effects of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae based on the Nrf2/ARE signaling pathway","doi":"10.5114/ceji.2025.152018","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic"},{"study":"Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2","doi":"10.3390/antiox11010156","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Effects of Sulforaphane Treatment on Skeletal Muscle from Exhaustive Exercise-Induced Inflammation and Oxidative Stress Through the Nrf2/HO-1 Signaling Pathway","doi":"10.3390/antiox14020210","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Sulforaphane alleviates hepatocyte pyroptosis via activating Nrf2-HO-1 signaling during septic acute liver injury","doi":"10.3389/fphar.2025.1690067","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Effect of Glucoraphanin on the Abundance of Nrf2 Regulated Genes Within Circulating Small Extracellular Vesicles: A Pilot Dietary Intervention","doi":"10.1002/mnfr.70397","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways","doi":"10.1186/s12931-015-0253-z","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Sulforaphane-Enriched Broccoli Sprouts Pretreated by Pulsed Electric Fields Reduces Neuroinflammation and Ameliorates Scopolamine-Induced Amnesia in Mouse Brain through Its Antioxidant Ability via Nrf2-HO-1 Activation","doi":"10.1155/2019/3549274","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic"},{"study":"Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway","doi":"10.1016/j.redox.2017.12.016","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"A proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway 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