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There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. Patients with ALS often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of\n                    <jats:italic>N<\/jats:italic>\n                    -acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models and induced pluripotent stem (iPS) cells derived from patients with ALS and SOD1\n                    <jats:sup>G93A<\/jats:sup>\n                    transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.\n                  <\/jats:p>\n                  <jats:p\/>\n                  <jats:p>Serum N-acyl taurines are potential prognostic biomarkers in ALS, and inhibition of fatty acid amide hydrolase (FAAH) represents a promising therapeutic strategy for the disease.<\/jats:p>","DOI":"10.1172\/jci.insight.198842","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:00:19Z","timestamp":1781193619000},"source":"Crossref","is-referenced-by-count":0,"title":["Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis"],"prefix":"10.1172","volume":"11","author":[{"given":"Daisuke","family":"Ito","sequence":"first","affiliation":[{"name":"Department of Neurology,"},{"name":"Department of Clinical Research 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