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In advanced stages or during acute complications, ALS can rapidly transition into a neurocritical state characterized by respiratory insufficiency, systemic dysfunction, and accelerated neurological decline. Although current management strategies for advanced-stage ALS are relatively well established, there remains a significant lack of targeted interventions aimed at preventing or attenuating neurocritical deterioration. This review systematically examines the pathophysiological mechanisms underlying neurocritical progression in ALS, including respiratory failure, metabolic imbalance, autonomic dysfunction, and multisystem involvement. We further evaluate emerging and potential therapeutic strategies designed to mitigate disease severity and stabilize critical neurological function. In addition, we analyze clinical and biological factors that increase susceptibility to neurocritical states and discuss evidence-based approaches to delay disease progression. By integrating clinical observations with mechanistic insights, this review aims to improve early recognition, optimize neurocritical management, and ultimately enhance outcomes for patients with\u00a0ALS.<\/jats:p>","DOI":"10.1515\/biol-2025-1323","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:59:32Z","timestamp":1778695172000},"source":"Crossref","is-referenced-by-count":0,"title":["Neurocritical progression in amyotrophic lateral sclerosis: pathological relevance and validation"],"prefix":"10.1515","volume":"21","author":[{"given":"Jiayue","family":"Pan","sequence":"first","affiliation":[{"name":"School of Medicine , Wuhan University of Science and Technology , Wuhan , Hubei Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9888-3320","authenticated-orcid":false,"given":"Chengyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine , Wuhan University of Science and Technology , Wuhan , Hubei Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine , Wuhan University of Science and Technology , Wuhan , Hubei Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Medicine , Wuhan University of Science and Technology , Wuhan , Hubei Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"2026051317592642007_j_biol-2025-1323_ref_001","doi-asserted-by":"crossref","unstructured":"Sances, S, Bruijn, LI, Chandran, S, Eggan, K, Ho, R, Klim, JR, et al.. 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