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Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1\u2013Nrf2 protein\u2013protein interaction inhibitors, dual Nrf2\/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2\u2019s therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots.<\/jats:p>","DOI":"10.3390\/ijms26209872","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:16Z","timestamp":1760107816000},"page":"9872","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Beyond Antioxidants: The Emerging Role of Nrf2 Activation in Amyotrophic Lateral Sclerosis (ALS)"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9887-5304","authenticated-orcid":false,"given":"Minoo","family":"Sharbafshaaer","sequence":"first","affiliation":[{"name":"First Division of Neurology and Neurophysiopathology, AOU Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Pepe","sequence":"additional","affiliation":[{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6048-9480","authenticated-orcid":false,"given":"Rosaria","family":"Notariale","sequence":"additional","affiliation":[{"name":"First Division of Neurology and Neurophysiopathology, AOU Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Canale","sequence":"additional","affiliation":[{"name":"First Division of Neurology and Neurophysiopathology, AOU Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioacchino","family":"Tedeschi","sequence":"additional","affiliation":[{"name":"First Division of Neurology and Neurophysiopathology, AOU Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Tessitore","sequence":"additional","affiliation":[{"name":"First Division of Neurology and Neurophysiopathology, AOU Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1726-7911","authenticated-orcid":false,"given":"Paolo","family":"Bergamo","sequence":"additional","affiliation":[{"name":"CNR-IBBR National Research Council, Institute of Biosciences and Bioresources, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3790-8018","authenticated-orcid":false,"given":"Francesca","family":"Trojsi","sequence":"additional","affiliation":[{"name":"First Division of Neurology and Neurophysiopathology, AOU Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17071","DOI":"10.1038\/nrdp.2017.71","article-title":"Amyotrophic lateral sclerosis","volume":"3","author":"Hardiman","year":"2017","journal-title":"Nat. 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