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Expecting a single pharmacologic intervention to meaningfully alter such a complex disease has proven overly optimistic and is reflected by the modest clinical benefits of approved monotherapies. This review outlines the mechanistic foundation and translational rationale for combination pharmacology in ALS. Drawing from paradigms in oncology, infectious disease, and other neurological disorders, it explores how rational multi-target strategies, whether synergistic, complementary, or pathway-divergent, may better address the multifactorial biology of ALS. The review also discusses recent mechanistic examples and design principles for advancing this therapeutic paradigm.<\/jats:p>","DOI":"10.3390\/ijms27167404","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:30:53Z","timestamp":1787131853000},"page":"7404","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combination Pharmacology for ALS: A Mechanistic Rationale"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4327-7774","authenticated-orcid":false,"given":"Jeffrey","family":"Rosenfeld","sequence":"first","affiliation":[{"name":"Center for Restorative Neurology, Department of Neurology, Loma Linda University Health, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6104-6377","authenticated-orcid":false,"given":"Shiran","family":"Salomon-Zimri","sequence":"additional","affiliation":[{"name":"NeuroSense Therapeutics, Herzliya 4672562, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferenc","family":"Tracik","sequence":"additional","affiliation":[{"name":"NeuroSense Therapeutics, Herzliya 4672562, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1016\/j.mayocp.2018.09.009","article-title":"Rethinking Amyotrophic Lateral Sclerosis","volume":"93","author":"Rosenfeld","year":"2018","journal-title":"Mayo Clin. 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