3b:I[281230,["/_next/static/immutable/chunks/0l5c-zsrs2aic.js","/_next/static/immutable/chunks/3_n0rk2989-8h.js","/_next/static/immutable/chunks/3ofw495lt1gr1.js","/_next/static/immutable/chunks/3tofdpg99uc12.js","/_next/static/immutable/chunks/2rzojj6zgb9d9.js","/_next/static/immutable/chunks/42jxjvozn2thc.js","/_next/static/immutable/chunks/1jp6nkbajpbfs.js","/_next/static/immutable/chunks/3jn_lf7v27x-6.js","/_next/static/immutable/chunks/33qq2-hg37d0b.js","/_next/static/immutable/chunks/15isb0svrppbz.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/0asz50g5_lfq9.js","/_next/static/immutable/chunks/30ia-cxa0yoyc.js","/_next/static/immutable/chunks/3ghibkczd0agr.js","/_next/static/immutable/chunks/20mjl75wrar8n.js","/_next/static/immutable/chunks/3nxreg9fiyt2y.js","/_next/static/immutable/chunks/0c04lgvo3p78i.js","/_next/static/immutable/chunks/1u78gf_avpn77.js"],"PaperListPageClient"] 3e:I[70339,["/_next/static/immutable/chunks/355lxm8rh3fxr.js"],"IconMark"] 3c:T817,Abstract M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NF-E2 p45-related factor 2-antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43 Q331K transgenic mouse model of ALS dosed subcutaneously at 5 mg/kg OD or 2.5 mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement. An oral dose response study of M102 in SOD1 G93A transgenic mice showed a dose-dependent improvement in CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies. A parallel program of work in vitro showed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic, C9orf72 and SOD1 ALS cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in these in vitro models. This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed. 3d:T5dd,GLP general toxicology studies in rats and NHPs were conducted at WuXi AppTec (Suzhou, China). The protocol and any amendments or procedures involving the care or use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) prior to the initiation of such procedures. A staff veterinarian monitored the study for animal welfare issues. All mouse studies were carried out under a UK Home Office project license (PP3890603) ethically reviewed and approved by the local ethics committee (University of Sheffield Animal Welfare and Ethical Review Body). All individuals held the appropriate UK Home Office personal license and had appropriate training for procedures. All work was carried out under the terms of the UK Animals (Scientific Procedures) Act 1986 and animals were housed and maintained in line with Home Office Code of Practice for House and Care of Animals Used in Scientific Procedures. All procedures were reviewed by the University of Sheffield. Human CNS post-mortem tissue was obtained from the Sheffield Brain Tissue Bank with Research Ethics Committee approval (Sheffield Brain Bank –SBB-, Ethics Committee reference 08/MRE00/103). Human CSF was obtained from the University of Sheffield Biorepository with Research Ethics Committee approval number STH16573. Fibroblasts were collected from skin biopsies donated by ALS patients and controls with informed consent (Ethical Committee approval references: 12/YH/0330; 16/LO/2136).28:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"NRF2 Activator: Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on NRF2 Activator (modality). Clinician-written summaries and actionable practice insights. Updated daily.\",\"url\":\"https://www.reachrx.ai/hub/tag/modality/NRF2%20Activator\",\"breadcrumb\":{\"@type\":\"BreadcrumbList\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https://www.reachrx.ai\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"Research Hub\",\"item\":\"https://www.reachrx.ai/hub\"},{\"@type\":\"ListItem\",\"position\":3,\"name\":\"Modalities\",\"item\":\"https://www.reachrx.ai/hub/tag/modality\"},{\"@type\":\"ListItem\",\"position\":4,\"name\":\"NRF2 Activator\",\"item\":\"https://www.reachrx.ai/hub/tag/modality/NRF2%20Activator\"}]}}"}}]],["$","$L3b",null,{"title":"NRF2 Activator: Research & Clinical Takeaways","description":"Review evidence by treatment modality: NRF2 Activator — concise summaries and practical next steps.","papers":[{"doi":"10.1016/j.freeradbiomed.2026.05.318","pmid":"42217684","title":"Circadian Rhythms, NRF2 Signalling and Redox Homeostasis: A Holy Grail for a Healthy Life Course?","journal_title":"Free Radical Biology and Medicine","journal_issn":"0891-5849","published_at":"2026-05-29T00:00:00.000Z","url":"https://doi.org/10.1016/j.freeradbiomed.2026.05.318","source_score":7,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-02T13:27:24.993Z","updated_at":"2026-06-02T13:27:24.993Z","tags":[{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"condition","value":"Ageing","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"condition","value":"Cancer","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"condition","value":"Cardiovascular Disease","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"condition","value":"Metabolic Disease","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"condition","value":"Neurodegenerative Disease","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"condition","value":"Oxidative Stress","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"modality","value":"Chronomedicine","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"modality","value":"NRF2 Activator","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"warning","value":"Full text was inaccessible due to a publisher paywall/captcha block; all structured data are derived exclusively from the abstract.","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"warning","value":"No sample size is reported — this is a narrative review synthesising in vitro, in vivo, and human studies without meta-analytic pooling.","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.318","tag_type":"warning","value":"Study design classified as 'Narrative Review' rather than 'Systematic Review' based on abstract language; no PRISMA or systematic search methodology is described.","value_numeric":null}],"summaries":{"what_studied":"This review integrates circadian clock biology, NRF2 signalling, and redox homeostasis into a unified 'circadian-NRF2-redox axis' framework, examining how their interplay shapes health from development through ageing, and how misalignment (e.g., shiftwork, light pollution, irregular sleep/feeding) drives oxidative stress and disease.","key_result":"The authors propose that circadian clocks rhythmically regulate NRF2 activity via redox-sensitive transcriptional/post-translational co-regulators, kinases, and miRNAs; and that NRF2-driven programmes (mitochondrial function, glutathione synthesis, xenobiotic defence) reinforce circadian robustness — with misalignment amplifying oxidative stress and accelerating age-related health decline.","limitations":"Full text was inaccessible; summary is based solely on the abstract. As a narrative review, no primary data or effect sizes are reported, and causal claims rely on synthesised experimental and observational evidence of variable quality.","practice_takeaway":"Clinicians should consider circadian misalignment (shiftwork, irregular sleep, erratic feeding) as a modifiable redox risk factor. Lifestyle interventions that regularise sleep/wake and feeding/fasting cycles, alongside time-of-day optimisation of NRF2-targeting therapies, may reduce chronic disease risk across the life course."}},{"doi":"10.1186/s13024-025-00908-y","pmid":"41188870","title":"M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis","journal_title":"Molecular Neurodegeneration","journal_issn":"1750-1326","published_at":"2025-11-05T00:00:00.000Z","url":"https://doi.org/10.1186/s13024-025-00908-y","source_score":1124,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2025-11-09","doi":"10.1186/s13024-025-00908-y","days":"30","issn":"1750-1326","rank":"1","field":"Clinical Medicine","score":"1124","category":"Neurosciences","categories":["Neurosciences"],"_categories":["Neurosciences"]},"pubmed":{"doi":"10.1186/s13024-025-00908-y","title":"M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis.","journal":"Molecular neurodegeneration","methods":"","results":"","abstract":"M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NF-E2 p45-related factor 2-antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43","keywords":["Amyotrophic lateral sclerosis","HSF1 activation","M102","NRF-2 activation","Neuroprotection","S-apomorphine"],"pubmed_id":"41188870","conclusions":"","publication_date":"2025-11-05T00:00:00"},"crossref":{"DOI":"10.1186/s13024-025-00908-y","URL":"https://doi.org/10.1186/s13024-025-00908-y","ISSN":["1750-1326"],"link":[{"URL":"https://link.springer.com/content/pdf/10.1186/s13024-025-00908-y.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https://link.springer.com/article/10.1186/s13024-025-00908-y/fulltext.html","content-type":"text/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https://link.springer.com/content/pdf/10.1186/s13024-025-00908-y.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":"1","score":1,"title":["M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis"],"author":[{"given":"Amy F.","family":"Keerie","sequence":"first","affiliation":[]},{"given":"Raquel Rua","family":"Martins","sequence":"additional","affiliation":[]},{"given":"Chloe F.","family":"Allen","sequence":"additional","affiliation":[]},{"given":"Katie","family":"Bowden","sequence":"additional","affiliation":[]},{"given":"Sufana","family":"Al Mashhadi","sequence":"additional","affiliation":[]},{"given":"Thomas","family":"Marlow","sequence":"additional","affiliation":[]},{"given":"Monika","family":"Myszczynska","sequence":"additional","affiliation":[]},{"given":"Nikitha","family":"Thakur","sequence":"additional","affiliation":[]},{"given":"Selina N.","family":"Beal","sequence":"additional","affiliation":[]},{"given":"Allan","family":"Shaw","sequence":"additional","affiliation":[]},{"given":"Shivani","family":"Suresh","sequence":"additional","affiliation":[]},{"given":"Scott N.","family":"McKinnon","sequence":"additional","affiliation":[]},{"given":"Johnathan","family":"Cooper-Knock","sequence":"additional","affiliation":[]},{"given":"Ryan J. H.","family":"West","sequence":"additional","affiliation":[]},{"given":"Sam","family":"Bonsall","sequence":"additional","affiliation":[]},{"given":"Alex","family":"Daniel","sequence":"additional","affiliation":[]},{"given":"Tyler","family":"Wells","sequence":"additional","affiliation":[]},{"given":"Vedanth","family":"Kumar","sequence":"additional","affiliation":[]},{"given":"Brittany C. S.","family":"Ellis","sequence":"additional","affiliation":[]},{"given":"Maureen","family":"Higgins","sequence":"additional","affiliation":[]},{"given":"Albena T.","family":"Dinkova-Kostova","sequence":"additional","affiliation":[]},{"given":"Tatyana A.","family":"Shelkovnikova","sequence":"additional","affiliation":[]},{"given":"Ira N.","family":"Kalfus","sequence":"additional","affiliation":[]},{"given":"Ning","family":"Shan","sequence":"additional","affiliation":[]},{"given":"Pamela J.","family":"Shaw","sequence":"additional","affiliation":[]},{"given":"Laura","family":"Ferraiuolo","sequence":"additional","affiliation":[]},{"given":"Richard J.","family":"Mead","sequence":"additional","affiliation":[]}],"funder":[{"id":[{"id":"10.13039/501100000265","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100014012","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100014012","name":"FightMND","doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100000005","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/501100000406","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/501100022572","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/501100022572","name":"NIHR Sheffield Biomedical Research Centre","doi-asserted-by":"publisher"}],"issued":{"date-parts":[[2025,11,4]]},"member":"297","prefix":"10.1186","source":"Crossref","volume":"20","created":{"date-time":"2025-11-04T09:55:51Z","timestamp":1762250151000,"date-parts":[[2025,11,4]]},"indexed":{"date-time":"2025-11-21T00:20:04Z","timestamp":1763684404458,"date-parts":[[2025,11,21]]},"license":[{"URL":"https://creativecommons.org/licenses/by/4.0","start":{"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000,"date-parts":[[2025,11,4]]},"delay-in-days":0,"content-version":"tdm"},{"URL":"https://creativecommons.org/licenses/by/4.0","start":{"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000,"date-parts":[[2025,11,4]]},"delay-in-days":0,"content-version":"vor"}],"subject":[],"abstract":"$3c","language":"en","relation":{},"resource":{"primary":{"URL":"https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-025-00908-y"}},"subtitle":[],"assertion":[{"name":"received","group":{"name":"ArticleHistory","label":"Article History"},"label":"Received","order":1,"value":"24 June 2025"},{"name":"accepted","group":{"name":"ArticleHistory","label":"Article History"},"label":"Accepted","order":2,"value":"9 October 2025"},{"name":"first_online","group":{"name":"ArticleHistory","label":"Article History"},"label":"First Online","order":3,"value":"4 November 2025"},{"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"},"order":1},{"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"},"order":2,"value":"$3d"},{"name":"Ethics","group":{"name":"EthicsHeading","label":"Patents relevant to M102"},"order":3,"value":"PCT/US2019/056996 - Treatment of Neurodegenerative diseases. Inventors: Ning Shan, Richard Mead, Laura Ferraiuolo, Pamela J Shaw. This covers the mechanism of action of a drug identified at SITraN for the treatment of neurodegenerative diseases, including ALS. Submitted in 2019. PCT/US2019/056998 - Treatment of Neurodegenerative diseases. Inventors: Laura Ferraiuolo, Ning Shan, Pamela J Shaw. This covers the specific properties of a neuroprotective compound identified at SITraN. Submitted in 2019. PCT/US2020/45321 - Pharmaceutical Composition For Use In The Treatment Of Neurological Diseases. Inventor: Ning Shan. This covers the pharmaceutical compositions and associated pharmacokinetics of a drug identified at SITraN. Submitted in 2019."},{"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"},"order":4,"value":"PJS is a member of the Scientific Advisory Board for Aclipse Therapeutics and PJS, RJM and LF are share-holders of Aclipse Therapeutics.NS and INK are employees of Aclipse Therapeutics."}],"deposited":{"date-time":"2025-11-04T21:02:55Z","timestamp":1762290175000,"date-parts":[[2025,11,4]]},"issn-type":[{"type":"electronic","value":"1750-1326"}],"published":{"date-parts":[[2025,11,4]]},"publisher":"Springer Science and Business Media LLC","reference":[{"DOI":"10.1001/jamaneurol.2019.2044","key":"908_CR1","year":"2019","issue":"11","author":"M Ryan","volume":"76","first-page":"1367","unstructured":"Ryan M, Heverin M, McLaughlin RL, Hardiman O. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367–74.","article-title":null,"journal-title":"JAMA Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1111/ene.14393","key":"908_CR2","year":"2020","issue":"10","author":"P Masrori","volume":"27","first-page":"1918","unstructured":"Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27(10):1918–29.","article-title":null,"journal-title":"Eur J Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1056/NEJM199403033300901","key":"908_CR3","year":"1994","issue":"9","author":"G Bensimon","volume":"330","first-page":"585","unstructured":"Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole study group. N Engl J Med. 1994;330(9):585–91.","article-title":null,"journal-title":"N Engl J Med","doi-asserted-by":"publisher"},{"DOI":"10.1016/S0140-6736(96)91680-3","key":"908_CR4","year":"1996","issue":"9013","author":"L Lacomblez","volume":"347","first-page":"1425","unstructured":"Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis/riluzole study group II. Lancet. 1996;347(9013):1425–31.","article-title":null,"journal-title":"Lancet","doi-asserted-by":"publisher"},{"DOI":"10.1016/S1474-4422(17)30115-1","key":"908_CR5","year":"2017","issue":"7","author":"ALSSG Writing Group, Edaravone","volume":"16","first-page":"505","unstructured":"Writing Group, Edaravone ALSSG. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(7):505–12.","article-title":null,"journal-title":"Lancet Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1056/NEJMoa2204705","key":"908_CR6","year":"2022","issue":"12","author":"TM Miller","volume":"387","first-page":"1099","unstructured":"Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, et al. Trial of antisense oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099–110.","article-title":null,"journal-title":"N Engl J Med","doi-asserted-by":"publisher"},{"DOI":"10.1016/bs.irn.2024.04.004","key":"908_CR7","year":"2024","issue":null,"author":"E Hobson","volume":"176","first-page":"119","unstructured":"Hobson E, McDermott C. Advances in symptom management and in monitoring disease progression in motor neuron disease. Int Rev Neurobiol. 2024;176:119–69.","article-title":null,"journal-title":"Int Rev Neurobiol","doi-asserted-by":"publisher"},{"DOI":"10.3109/21678421.2014.951946","key":"908_CR8","year":null,"issue":null,"author":null,"volume":null,"first-page":null,"unstructured":"Obermann M, Lyon M. Financial cost of amyotrophic lateral sclerosis: a case study. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(1–2):54–7.9.","article-title":null,"journal-title":null,"doi-asserted-by":"crossref"},{"DOI":"10.1038/s41573-022-00612-2","key":"908_CR9","year":"2023","issue":"3","author":"RJ Mead","volume":"22","first-page":"185","unstructured":"Mead RJ, Shan N, Reiser HJ, Marshall F, Shaw PJ. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185–212.","article-title":null,"journal-title":"Nat Rev Drug Discov","doi-asserted-by":"publisher"},{"DOI":"10.1073/pnas.1314085111","key":"908_CR10","year":"2014","issue":"2","author":"K Meyer","volume":"111","first-page":"829","unstructured":"Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, McElroy S, Renusch S, et al. Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A. 2014;111(2):829–32.","article-title":null,"journal-title":"Proc Natl Acad Sci U S A","doi-asserted-by":"publisher"},{"DOI":"10.3390/ijms242015430","key":"908_CR11","year":null,"issue":null,"author":null,"volume":null,"first-page":null,"unstructured":"Provenzano F, Torazza C, Bonifacino T, Bonanno G, Milanese M. The key role of astrocytes in amyotrophic lateral sclerosis and their commitment to glutamate excitotoxicity. Int J Mol Sci. 2023;24(20).","article-title":null,"journal-title":null,"doi-asserted-by":"crossref"},{"DOI":"10.3389/fncel.2020.581950","key":"908_CR12","year":"2020","issue":null,"author":"CJ Jagaraj","volume":"14","first-page":"581950","unstructured":"Jagaraj CJ, Parakh S, Atkin JD. Emerging evidence highlighting the importance of redox dysregulation in the pathogenesis of amyotrophic lateral sclerosis (ALS). Front Cell Neurosci. 2020;14:581950.","article-title":null,"journal-title":"Front Cell Neurosci","doi-asserted-by":"publisher"},{"DOI":"10.1097/WCO.0000000000000983","key":"908_CR13","year":"2021","issue":"5","author":"SH Appel","volume":"34","first-page":"765","unstructured":"Appel SH, Beers DR, Zhao W. Amyotrophic lateral sclerosis is a systemic disease: peripheral contributions to inflammation-mediated neurodegeneration. Curr Opin Neurol. 2021;34(5):765–72.","article-title":null,"journal-title":"Curr Opin Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1097/WCO.0000000000001279","key":"908_CR14","year":"2024","issue":"5","author":"AD Calma","volume":"37","first-page":"585","unstructured":"Calma AD, Pavey N, Menon P, Vucic S. Neuroinflammation in amyotrophic lateral sclerosis: pathogenic insights and therapeutic implications. Curr Opin Neurol. 2024;37(5):585–92.","article-title":null,"journal-title":"Curr Opin Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1016/bs.irn.2024.04.006","key":"908_CR15","year":"2024","issue":null,"author":"J Lee","volume":"176","first-page":"269","unstructured":"Lee J, Pye N, Ellis L, Vos K, Mortiboys H. Evidence of mitochondrial dysfunction in ALS and methods for measuring in model systems. Int Rev Neurobiol. 2024;176:269–325.","article-title":null,"journal-title":"Int Rev Neurobiol","doi-asserted-by":"publisher"},{"DOI":"10.3389/fnmol.2017.00123","key":"908_CR16","year":"2017","issue":null,"author":"CP Webster","volume":"10","first-page":"123","unstructured":"Webster CP, Smith EF, Shaw PJ, De Vos KJ. Protein homeostasis in amyotrophic lateral sclerosis: therapeutic opportunities? Front Mol Neurosci. 2017;10:123.","article-title":null,"journal-title":"Front Mol Neurosci","doi-asserted-by":"publisher"},{"DOI":"10.1016/S1474-4422(14)70129-2","key":"908_CR17","year":"2014","issue":"11","author":"H Mitsumoto","volume":"13","first-page":"1127","unstructured":"Mitsumoto H, Brooks BR, Silani V. Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol. 2014;13(11):1127–38.","article-title":null,"journal-title":"Lancet Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1038/s41573-018-0008-x","key":"908_CR18","year":"2019","issue":"4","author":"A Cuadrado","volume":"18","first-page":"295","unstructured":"Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019;18(4):295–317.","article-title":null,"journal-title":"Nat Rev Drug Discov","doi-asserted-by":"publisher"},{"DOI":"10.3390/antiox12020366","key":"908_CR19","year":null,"issue":null,"author":null,"volume":null,"first-page":null,"unstructured":"McCord JM, Gao B, Hybertson BM. The complex genetic and epigenetic regulation of the Nrf2 pathways: A review. Antioxid (Basel). 2023;12(2).","article-title":null,"journal-title":null,"doi-asserted-by":"crossref"},{"DOI":"10.1016/j.arr.2022.101756","key":"908_CR20","year":"2022","issue":null,"author":"M George","volume":"82","first-page":"101756","unstructured":"George M, Tharakan M, Culberson J, Reddy AP, Reddy PH. Role of Nrf2 in aging, alzheimer’s and other neurodegenerative diseases. Ageing Res Rev. 2022;82:101756.","article-title":null,"journal-title":"Ageing Res Rev","doi-asserted-by":"publisher"},{"DOI":"10.1101/gad.13.1.76","key":"908_CR21","year":"1999","issue":"1","author":"K Itoh","volume":"13","first-page":"76","unstructured":"Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13(1):76–86.","article-title":null,"journal-title":"Genes Dev","doi-asserted-by":"publisher"},{"DOI":"10.1093/brain/awh503","key":"908_CR22","year":"2005","issue":"Pt 7","author":"J Kirby","volume":"128","first-page":"1686","unstructured":"Kirby J, Halligan E, Baptista MJ, Allen S, Heath PR, Holden H, et al. Mutant SOD1 alters the motor neuronal transcriptome: implications for Familial ALS. Brain. 2005;128(Pt 7):1686–706.","article-title":null,"journal-title":"Brain","doi-asserted-by":"publisher"},{"DOI":"10.1093/brain/awl118","key":"908_CR23","year":"2006","issue":"Pt 7","author":"CA Wood-Allum","volume":"129","first-page":"1693","unstructured":"Wood-Allum CA, Barber SC, Kirby J, Heath P, Holden H, Mead R, et al. Impairment of mitochondrial anti-oxidant defence in SOD1-related motor neuron injury and amelioration by Ebselen. Brain. 2006;129(Pt 7):1693–709.","article-title":null,"journal-title":"Brain","doi-asserted-by":"publisher"},{"DOI":"10.1523/JNEUROSCI.0823-07.2007","key":"908_CR24","year":"2007","issue":"29","author":"M Pehar","volume":"27","first-page":"7777","unstructured":"Pehar M, Vargas MR, Robinson KM, Cassina P, Diaz-Amarilla PJ, Hagen TM, et al. Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J Neurosci. 2007;27(29):7777–85.","article-title":null,"journal-title":"J Neurosci","doi-asserted-by":"publisher"},{"DOI":"10.1097/NEN.0b013e31818b4906","key":"908_CR25","year":"2008","issue":"11","author":"A Sarlette","volume":"67","first-page":"1055","unstructured":"Sarlette A, Krampfl K, Grothe C, Neuhoff N, Dengler R, Petri S. Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2008;67(11):1055–62.","article-title":null,"journal-title":"J Neuropathol Exp Neurol","doi-asserted-by":"publisher"},{"DOI":"10.3109/21678421.2013.839708","key":"908_CR26","year":"2014","issue":"1–2","author":"P Bergstrom","volume":"15","first-page":"130","unstructured":"Bergstrom P, von Otter M, Nilsson S, Nilsson AC, Nilsson M, Andersen PM, et al. Association of NFE2L2 and KEAP1 haplotypes with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15(1–2):130–7.","article-title":null,"journal-title":"Amyotroph Lateral Scler Frontotemporal Degener","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.freeradbiomed.2021.07.022","key":"908_CR27","year":"2021","issue":null,"author":"J Jimenez-Villegas","volume":"173","first-page":"125","unstructured":"Jimenez-Villegas J, Ferraiuolo L, Mead RJ, Shaw PJ, Cuadrado A, Rojo AI. NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS. Free Radic Biol Med. 2021;173:125–41.","article-title":null,"journal-title":"Free Radic Biol Med","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.freeradbiomed.2013.04.018","key":"908_CR28","year":"2013","issue":null,"author":"RJ Mead","volume":"61","first-page":"438","unstructured":"Mead RJ, Higginbottom A, Allen SP, Kirby J, Bennett E, Barber SC, et al. S[+] apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis. Free Radic Biol Med. 2013;61:438–52.","article-title":null,"journal-title":"Free Radic Biol Med","doi-asserted-by":"publisher"},{"DOI":"10.1016/0014-2999(83)90394-1","key":"908_CR29","year":"1983","issue":"1","author":"J Lehmann","volume":"88","first-page":"81","unstructured":"Lehmann J, Smith RV, Langer SZ. Stereoisomers of apomorphine differ in affinity and intrinsic activity at presynaptic dopamine receptors modulating [3H]dopamine and [3H]acetylcholine release in slices of Cat caudate. Eur J Pharmacol. 1983;88(1):81–8.","article-title":null,"journal-title":"Eur J Pharmacol","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.nbd.2006.12.015","key":"908_CR30","year":"2007","issue":"1","author":"M Benatar","volume":"26","first-page":"1","unstructured":"Benatar M. Lost in translation: treatment trials in the SOD1 mouse and in human ALS. Neurobiol Dis. 2007;26(1):1–13.","article-title":null,"journal-title":"Neurobiol Dis","doi-asserted-by":"publisher"},{"DOI":null,"key":"908_CR31","year":"2008","issue":"7205","author":"J Schnabel","volume":"454","first-page":"682","unstructured":"Schnabel J, Neuroscience. Standard Model Nat. 2008;454(7205):682–5.","article-title":null,"journal-title":"Standard Model Nat","doi-asserted-by":null},{"DOI":"10.1038/s41598-021-96122-z","key":"908_CR32","year":"2021","issue":"1","author":"JA Watkins","volume":"11","first-page":"16659","unstructured":"Watkins JA, Alix JJP, Shaw PJ, Mead RJ. Extensive phenotypic characterisation of a human TDP-43(Q331K) Transgenic mouse model of amyotrophic lateral sclerosis (ALS). Sci Rep. 2021;11(1):16659.","article-title":null,"journal-title":"Sci Rep","doi-asserted-by":"publisher"},{"DOI":"10.1111/febs.13999","key":"908_CR33","year":"2017","issue":"11","author":"S Dayalan Naidu","volume":"284","first-page":"1606","unstructured":"Dayalan Naidu S, Dinkova-Kostova AT. Regulation of the mammalian heat shock factor 1. FEBS J. 2017;284(11):1606–27.","article-title":null,"journal-title":"FEBS J","doi-asserted-by":"publisher"},{"DOI":"10.1111/febs.14379","key":"908_CR34","year":"2018","issue":"19","author":"AT Dinkova-Kostova","volume":"285","first-page":"3576","unstructured":"Dinkova-Kostova AT, Kostov RV, Kazantsev AG. The role of Nrf2 signaling in counteracting neurodegenerative diseases. FEBS J. 2018;285(19):3576–90.","article-title":null,"journal-title":"FEBS J","doi-asserted-by":"publisher"},{"DOI":"10.1016/S1474-4422(16)00099-5","key":"908_CR35","year":"2016","issue":"7","author":"HH Kampinga","volume":"15","first-page":"748","unstructured":"Kampinga HH, Bergink S. Heat shock proteins as potential targets for protective strategies in neurodegeneration. Lancet Neurol. 2016;15(7):748–59.","article-title":null,"journal-title":"Lancet Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1038/s41398-020-01078-9","key":"908_CR36","year":"2020","issue":"1","author":"E Kim","volume":"10","first-page":"377","unstructured":"Kim E, White MA, Phillips BU, Lopez-Cruz L, Kim H, Heath CJ, et al. Coexistence of perseveration and apathy in the TDP-43(Q331K) knock-in mouse model of ALS-FTD. Transl Psychiatry. 2020;10(1):377.","article-title":null,"journal-title":"Transl Psychiatry","doi-asserted-by":"publisher"},{"DOI":"10.1111/bpa.12351","key":"908_CR37","year":"2016","issue":"2","author":"G Nardo","volume":"26","first-page":"237","unstructured":"Nardo G, Trolese MC, Tortarolo M, Vallarola A, Freschi M, Pasetto L, et al. New insights on the mechanisms of disease course variability in ALS from mutant SOD1 mouse models. Brain Pathol. 2016;26(2):237–47.","article-title":null,"journal-title":"Brain Pathol","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.isci.2020.101087","key":"908_CR38","year":"2020","issue":"5","author":"S Scaricamazza","volume":"23","first-page":"101087","unstructured":"Scaricamazza S, Salvatori I, Giacovazzo G, Loeffler JP, Rene F, Rosina M, et al. Skeletal-Muscle metabolic reprogramming in ALS-SOD1(G93A) mice predates disease onset and is a promising therapeutic target. iScience. 2020;23(5):101087.","article-title":null,"journal-title":"iScience","doi-asserted-by":"publisher"},{"DOI":"10.1177/0091270008320369","key":"908_CR39","year":"2008","issue":"10","author":"K Goteti","volume":"48","first-page":"1226","unstructured":"Goteti K, Brassil PJ, Good SS, Garner CE. Estimation of human drug clearance using multiexponential techniques. J Clin Pharmacol. 2008;48(10):1226–36.","article-title":null,"journal-title":"J Clin Pharmacol","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.freeradbiomed.2009.11.018","key":"908_CR40","year":"2010","issue":"5","author":"SC Barber","volume":"48","first-page":"629","unstructured":"Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic Biol Med. 2010;48(5):629–41.","article-title":null,"journal-title":"Free Radic Biol Med","doi-asserted-by":"publisher"},{"DOI":"10.3389/fgene.2018.00712","key":"908_CR41","year":"2018","issue":null,"author":"Z Butti","volume":"9","first-page":"712","unstructured":"Butti Z, Patten SA. RNA dysregulation in amyotrophic lateral sclerosis. Front Genet. 2018;9:712.","article-title":null,"journal-title":"Front Genet","doi-asserted-by":"publisher"},{"DOI":"10.3389/fmolb.2020.00184","key":"908_CR42","year":"2020","issue":null,"author":"Z Li","volume":"7","first-page":"184","unstructured":"Li Z, Chen X, Liu Z, Ye W, Li L, Qian L, et al. Recent advances: molecular mechanism of RNA oxidation and its role in various diseases. Front Mol Biosci. 2020;7:184.","article-title":null,"journal-title":"Front Mol Biosci","doi-asserted-by":"publisher"},{"DOI":"10.1017/S1462399409001094","key":"908_CR43","year":"2009","issue":null,"author":"MR Vargas","volume":"11","first-page":"e17","unstructured":"Vargas MR, Johnson JA. The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev Mol Med. 2009;11:e17.","article-title":null,"journal-title":"Expert Rev Mol Med","doi-asserted-by":"publisher"},{"DOI":"10.1111/acel.13281","key":"908_CR44","year":"2021","issue":"1","author":"N Gatto","volume":"20","first-page":"e13281","unstructured":"Gatto N, Dos Santos Souza C, Shaw AC, Bell SM, Myszczynska MA, Powers S, et al. Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease. Aging Cell. 2021;20(1):e13281.","article-title":null,"journal-title":"Aging Cell","doi-asserted-by":"publisher"},{"DOI":"10.1002/ana.21147","key":"908_CR45","year":"2007","issue":"5","author":"IR Mackenzie","volume":"61","first-page":"427","unstructured":"Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007;61(5):427–34.","article-title":null,"journal-title":"Ann Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1038/s41598-018-31773-z","key":"908_CR46","year":"2018","issue":"1","author":"B Pare","volume":"8","first-page":"14223","unstructured":"Pare B, Lehmann M, Beaudin M, Nordstrom U, Saikali S, Julien JP, et al. Misfolded SOD1 pathology in sporadic amyotrophic lateral sclerosis. Sci Rep. 2018;8(1):14223.","article-title":null,"journal-title":"Sci Rep","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.nbd.2025.107124","key":"908_CR47","year":"2025","issue":null,"author":"T Marlow","volume":"216","first-page":"107124","unstructured":"Marlow T, Bowden K, Collins M, Shaw PJ. The potential role of misfolded wild-type SOD1 protein in sporadic amyotrophic lateral sclerosis (ALS): a review of the evidence. Neurobiol Disease. 2025;216:107124.","article-title":null,"journal-title":"Neurobiol Disease","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.nbd.2023.106245","key":"908_CR48","year":"2023","issue":null,"author":"MC Cao","volume":"185","first-page":"106245","unstructured":"Cao MC, Ryan B, Wu J, Curtis MA, Faull RLM, Dragunow M, Scotter EL. A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue. Neurobiol Dis. 2023;185:106245.","article-title":null,"journal-title":"Neurobiol Dis","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.celrep.2024.114421","key":"908_CR49","year":"2024","issue":"7","author":"WP Huang","volume":"43","first-page":"114421","unstructured":"Huang WP, Ellis BCS, Hodgson RE, Sanchez Avila A, Kumar V, Rayment J, Moll T, Shelkovnikova TA. Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion. Cell Rep. 2024;43(7):114421.","article-title":null,"journal-title":"Cell Rep","doi-asserted-by":"publisher"},{"DOI":"10.1371/journal.pone.0023244","key":"908_CR50","year":"2011","issue":"8","author":"RJ Mead","volume":"6","first-page":"e23244","unstructured":"Mead RJ, Bennett EJ, Kennerley AJ, Sharp P, Sunyach C, Kasher P, et al. Optimised and rapid pre-clinical screening in the SOD1(G93A) Transgenic mouse model of amyotrophic lateral sclerosis (ALS). PLoS ONE. 2011;6(8):e23244.","article-title":null,"journal-title":"PLoS ONE","doi-asserted-by":"publisher"},{"DOI":"10.1073/pnas.1222809110","key":"908_CR51","year":"2013","issue":"8","author":"ES Arnold","volume":"110","first-page":"E736","unstructured":"Arnold ES, Ling SC, Huelga SC, Lagier-Tourenne C, Polymenidou M, Ditsworth D, et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A. 2013;110(8):E736–45.","article-title":null,"journal-title":"Proc Natl Acad Sci U S A","doi-asserted-by":"publisher"},{"DOI":"10.1016/bs.irn.2024.04.003","key":"908_CR52","year":"2024","issue":null,"author":"LJ Evans","volume":"176","first-page":"327","unstructured":"Evans LJ, O’Brien D, Shaw PJ. Current neuroprotective therapies and future prospects for motor neuron disease. Int Rev Neurobiol. 2024;176:327–84.","article-title":null,"journal-title":"Int Rev Neurobiol","doi-asserted-by":"publisher"},{"DOI":"10.1038/nrdp.2017.71","key":"908_CR53","year":"2017","issue":null,"author":"O Hardiman","volume":"3","first-page":"17071","unstructured":"Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071.","article-title":null,"journal-title":"Nat Rev Dis Primers","doi-asserted-by":"publisher"},{"DOI":"10.1007/s00401-018-1933-9","key":"908_CR54","year":"2019","issue":"5","author":"ME McCauley","volume":"137","first-page":"715","unstructured":"McCauley ME, Baloh RH. Inflammation in ALS/FTD pathogenesis. Acta Neuropathol. 2019;137(5):715–30.","article-title":null,"journal-title":"Acta Neuropathol","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.neulet.2017.06.052","key":"908_CR55","year":"2019","issue":null,"author":"EF Smith","volume":"710","first-page":"132933","unstructured":"Smith EF, Shaw PJ, De Vos KJ. The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett. 2019;710:132933.","article-title":null,"journal-title":"Neurosci Lett","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.nbd.2018.07.005","key":"908_CR56","year":"2019","issue":null,"author":"CS Evans","volume":"122","first-page":"35","unstructured":"Evans CS, Holzbaur ELF. Autophagy and mitophagy in ALS. Neurobiol Dis. 2019;122:35–40.","article-title":null,"journal-title":"Neurobiol Dis","doi-asserted-by":"publisher"},{"DOI":"10.3390/antiox13030262","key":"908_CR57","year":null,"issue":null,"author":null,"volume":null,"first-page":null,"unstructured":"Bonay M. Molecular targets of oxidative stress: focus on the Nrf2 signaling pathway in health and disease. Antioxid (Basel). 2024;13(3).","article-title":null,"journal-title":null,"doi-asserted-by":"crossref"},{"DOI":"10.22541/au.168872044.49044735/v1","key":"908_CR58","year":null,"issue":null,"author":null,"volume":null,"first-page":null,"unstructured":"Murakami S, Kusano Y, Okazaki K, Akaike T, Motohashi H. NRF2 signalling in cytoprotection and metabolism. Br J Pharmacol. 2023:1–14.","article-title":null,"journal-title":null,"doi-asserted-by":"crossref"},{"DOI":"10.3389/fphar.2024.1437939","key":"908_CR59","year":"2024","issue":null,"author":"C Mayer","volume":"15","first-page":"1437939","unstructured":"Mayer C, Riera-Ponsati L, Kauppinen S, Klitgaard H, Erler JT, Hansen SN. Targeting the NRF2 pathway for disease modification in neurodegenerative diseases: mechanisms and therapeutic implications. Front Pharmacol. 2024;15:1437939.","article-title":null,"journal-title":"Front Pharmacol","doi-asserted-by":"publisher"},{"DOI":"10.1074/jbc.M300931200","key":"908_CR60","year":"2003","issue":"24","author":"M McMahon","volume":"278","first-page":"21592","unstructured":"McMahon M, Itoh K, Yamamoto M, Hayes JD. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003;278(24):21592–600.","article-title":null,"journal-title":"J Biol Chem","doi-asserted-by":"publisher"},{"DOI":"10.1074/jbc.M500166200","key":"908_CR61","year":"2005","issue":"17","author":"S Dhakshinamoorthy","volume":"280","first-page":"16891","unstructured":"Dhakshinamoorthy S, Jain AK, Bloom DA, Jaiswal AK. Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem. 2005;280(17):16891–900.","article-title":null,"journal-title":"J Biol Chem","doi-asserted-by":"publisher"},{"DOI":"10.1186/s13024-021-00479-8","key":"908_CR62","year":"2021","issue":"1","author":"S Bono","volume":"16","first-page":"71","unstructured":"Bono S, Feligioni M, Corbo M. Impaired antioxidant KEAP1-NRF2 system in amyotrophic lateral sclerosis: NRF2 activation as a potential therapeutic strategy. Mol Neurodegener. 2021;16(1):71.","article-title":null,"journal-title":"Mol Neurodegener","doi-asserted-by":"publisher"},{"DOI":"10.1134/S0006297922010060","key":"908_CR63","year":"2022","issue":"1","author":"GA Shilovsky","volume":"87","first-page":"70","unstructured":"Shilovsky GA. Lability of the Nrf2/Keap/ARE cell defense system in different models of cell aging and Age-Related pathologies. Biochem (Mosc). 2022;87(1):70–85.","article-title":null,"journal-title":"Biochem (Mosc)","doi-asserted-by":"publisher"},{"DOI":"10.1134/S0006297922120057","key":"908_CR64","year":"2022","issue":"12","author":"GA Shilovsky","volume":"87","first-page":"1477","unstructured":"Shilovsky GA, Ashapkin VV. Transcription factor Nrf2 and Mitochondria - Friends or foes in the regulation of aging rate. Biochem (Mosc). 2022;87(12):1477–86.","article-title":null,"journal-title":"Biochem (Mosc)","doi-asserted-by":"publisher"},{"DOI":"10.1523/JNEUROSCI.23-13-05789.2003","key":"908_CR65","year":"2003","issue":"13","author":"Z Batulan","volume":"23","first-page":"5789","unstructured":"Batulan Z, Shinder GA, Minotti S, He BP, Doroudchi MM, Nalbantoglu J, et al. High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J Neurosci. 2003;23(13):5789–98.","article-title":null,"journal-title":"J Neurosci","doi-asserted-by":"publisher"},{"DOI":"10.1093/brain/aww028","key":"908_CR66","year":"2016","issue":"Pt 5","author":"HJ Chen","volume":"139","first-page":"1417","unstructured":"Chen HJ, Mitchell JC, Novoselov S, Miller J, Nishimura AL, Scotter EL, et al. The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis. Brain. 2016;139(Pt 5):1417–32.","article-title":null,"journal-title":"Brain","doi-asserted-by":"publisher"},{"DOI":"10.1038/nrd3453","key":"908_CR67","year":"2011","issue":"12","author":"DW Neef","volume":"10","first-page":"930","unstructured":"Neef DW, Jaeger AM, Thiele DJ. Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat Rev Drug Discov. 2011;10(12):930–44.","article-title":null,"journal-title":"Nat Rev Drug Discov","doi-asserted-by":"publisher"},{"DOI":"10.1007/s13311-022-01297-6","key":"908_CR68","year":"2022","issue":"4","author":"MP Coleman","volume":"19","first-page":"1133","unstructured":"Coleman MP. Axon biology in ALS: mechanisms of axon degeneration and prospects for therapy. Neurotherapeutics. 2022;19(4):1133–44.","article-title":null,"journal-title":"Neurotherapeutics","doi-asserted-by":"publisher"},{"DOI":"10.1002/acn3.51446","key":"908_CR69","year":"2021","issue":"10","author":"S Vucic","volume":"8","first-page":"1991","unstructured":"Vucic S, Henderson RD, Mathers S, Needham M, Schultz D, Kiernan MC, et al. Safety and efficacy of dimethyl fumarate in ALS: randomised controlled study. Ann Clin Transl Neurol. 2021;8(10):1991–9.","article-title":null,"journal-title":"Ann Clin Transl Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1002/ana.25934","key":"908_CR70","year":"2021","issue":"2","author":"DR Lynch","volume":"89","first-page":"212","unstructured":"Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, et al. Safety and efficacy of Omaveloxolone in Friedreich ataxia (MOXIe Study). Ann Neurol. 2021;89(2):212–25.","article-title":null,"journal-title":"Ann Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1159/000529471","key":"908_CR71","year":"2023","issue":"8","author":"P Ruggenenti","volume":"147","first-page":"465","unstructured":"Ruggenenti P. The CARDINAL trial of Bardoxolone Methyl in Alport syndrome: when marketing interests prevail over patients clinical needs. Nephron. 2023;147(8):465–9.","article-title":null,"journal-title":"Nephron","doi-asserted-by":"publisher"},{"DOI":"10.1016/S1474-4422(24)00134-0","key":"908_CR72","year":"2024","issue":"7","author":"M Benatar","volume":"23","first-page":"687","unstructured":"Benatar M, Hansen T, Rom D, Geist MA, Blaettler T, Camu W, et al. Safety and efficacy of Arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Neurol. 2024;23(7):687–99.","article-title":null,"journal-title":"Lancet Neurol","doi-asserted-by":"publisher"},{"DOI":"10.1212/WNL.0000000000004960","key":"908_CR73","year":"2018","issue":"7","author":"M Benatar","volume":"90","first-page":"e565","unstructured":"Benatar M, Wuu J, Andersen PM, Atassi N, David W, Cudkowicz M, et al. Randomized, double-blind, placebo-controlled trial of Arimoclomol in rapidly progressive SOD1 ALS. Neurology. 2018;90(7):e565–74.","article-title":null,"journal-title":"Neurology","doi-asserted-by":"publisher"},{"DOI":"10.21769/BioProtoc.3353","key":"908_CR74","year":null,"issue":null,"author":null,"volume":null,"first-page":null,"unstructured":"Stopford MJ, Allen SP, Ferraiuolo L. A High-throughput and pathophysiologically relevant Astrocyte-motor neuron Co-culture assay for amyotrophic lateral sclerosis therapeutic discovery. Bio Protoc. 2019;9(17).","article-title":null,"journal-title":null,"doi-asserted-by":"crossref"}],"short-title":[],"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"update-policy":"https://doi.org/10.1007/springer_crossmark_policy","alternative-id":["908"],"article-number":"118","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"original-title":[],"container-title":["Molecular Neurodegeneration"],"reference-count":74,"published-online":{"date-time":null,"timestamp":null,"date-parts":[[2025,11,4]]},"references-count":74,"short-container-title":["Mol Neurodegeneration"],"is-referenced-by-count":0},"unpaywall":{"doi":"10.1186/s13024-025-00908-y","is_oa":true,"title":"M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis","updated":"2025-11-09T00:29:14+00:00","published_date":"2025-11-04","best_oa_location":{"url":"https://molecularneurodegeneration.biomedcentral.com/counter/pdf/10.1186/s13024-025-00908-y","pmh_id":null,"url_for_pdf":"https://molecularneurodegeneration.biomedcentral.com/counter/pdf/10.1186/s13024-025-00908-y","url_for_landing_page":"https://doi.org/10.1186/s13024-025-00908-y"}}},"created_at":"2025-12-04T03:42:26.941Z","updated_at":"2025-12-08T12:24:58.509Z","tags":[{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"generic","value":"M102","value_numeric":null},{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"modality","value":"HSF1 Activator","value_numeric":null},{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"modality","value":"NRF2 Activator","value_numeric":null},{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"study_design","value":"Preclinical Study","value_numeric":null},{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"warning","value":"Details on specific models, dosing, and sample sizes were not provided in the source text.","value_numeric":null},{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"warning","value":"Only a partial abstract was available; no quantitative outcomes were provided in the text.","value_numeric":null},{"paper_doi":"10.1186/s13024-025-00908-y","tag_type":"warning","value":"The study appears preclinical; design labeling may not match standard clinical categories.","value_numeric":null}],"summaries":{"what_studied":"Evaluated M102, a CNS-penetrant small-molecule electrophile that activates NRF2-ARE and HSE gene transcription in vivo, for neuroprotection in cell and animal models of amyotrophic lateral sclerosis.","limitations":"Evidence is limited to preclinical cell and animal models with no human clinical data reported.","practice_takeaway":"M102 shows preclinical neuroprotection via dual activation of NRF2 and HSF1 pathways in ALS models, but this is not ready for clinical use until human studies are available."}}],"initialOffset":2,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"modality","value":"NRF2 Activator"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Modalities","href":"/hub/tag/modality"},{"name":"NRF2 Activator"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"modality","hub_tag_value":"NRF2 Activator"}}}]] 2b:null 2f:[["$","title","0",{"children":"NRF2 Activator: Research & Clinical Takeaways | ReachRx"}],["$","meta","1",{"name":"description","content":"Explore peer-reviewed papers on NRF2 Activator (modality). Clinician-written summaries and actionable practice insights. Updated daily."}],["$","meta","2",{"name":"apple-mobile-web-app-capable","content":"yes"}],["$","meta","3",{"name":"msapplication-config","content":"/browserconfig.xml"}],["$","meta","4",{"name":"msapplication-tap-highlight","content":"no"}],["$","link","5",{"rel":"canonical","href":"https://www.reachrx.ai/hub/tag/modality/NRF2%20Activator"}],["$","meta","6",{"name":"format-detection","content":"telephone=no"}],["$","meta","7",{"name":"mobile-web-app-capable","content":"yes"}],["$","meta","8",{"name":"apple-mobile-web-app-status-bar-style","content":"black-translucent"}],["$","meta","9",{"property":"og:title","content":"NRF2 Activator: Research & Clinical Takeaways | ReachRx"}],["$","meta","10",{"property":"og:description","content":"Explore peer-reviewed papers on NRF2 Activator (modality). Clinician-written summaries and actionable practice insights. Updated daily."}],["$","meta","11",{"property":"og:url","content":"https://www.reachrx.ai/hub/tag/modality/NRF2%20Activator"}],["$","meta","12",{"property":"og:site_name","content":"ReachRx"}],["$","meta","13",{"property":"og:locale","content":"en_US"}],["$","meta","14",{"property":"og:image","content":"https://www.reachrx.ai/reachrx_branding/reachrx-logo-metaimage.png"}],["$","meta","15",{"property":"og:image:type","content":"image/png"}],["$","meta","16",{"property":"og:image:width","content":"1200"}],["$","meta","17",{"property":"og:image:height","content":"630"}],["$","meta","18",{"property":"og:type","content":"website"}],["$","meta","19",{"name":"twitter:card","content":"summary_large_image"}],["$","meta","20",{"name":"twitter:creator","content":"@Reach_Rx"}],["$","meta","21",{"name":"twitter:title","content":"NRF2 Activator: Research & Clinical Takeaways | ReachRx"}],["$","meta","22",{"name":"twitter:description","content":"Explore peer-reviewed papers on NRF2 Activator (modality). Clinician-written summaries and actionable practice insights. Updated daily."}],["$","meta","23",{"name":"twitter:image","content":"https://www.reachrx.ai/reachrx_branding/reachrx-logo-metaimage.png"}],["$","link","24",{"rel":"shortcut icon","href":"/favicon.ico"}],["$","link","25",{"rel":"apple-touch-icon","href":"/apple-touch-icon.png","sizes":"180x180"}],["$","link","26",{"rel":"mask-icon","href":"/safari-pinned-tab.svg","color":"#000000"}],["$","$L3e","27",{}]]

Papers

Papers