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They exert pleiotropic effects including anti\u2010inflammation, anti\u2010apoptosis, antioxidant activity, and vasodilation. Soluble epoxide hydrolase (sEH) rapidly hydrolyzes EETs to inactive diols, and its inhibition has emerged as a promising strategy to potentiate EET\u2010mediated benefits. This review synthesizes current evidence on the roles and mechanisms of EETs and sEH in major neurological disorders and discusses translational challenges and future directions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A narrative review was conducted to synthesize evidence on the biosynthesis and metabolism of EETs, the expression and regulation of brain cytochrome P450 epoxygenases and sEH, the neuroprotective effects of EETs, and the therapeutic potential of sEH inhibitors, and to identify current limitations and future strategies for sEH\u2010targeted therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>EETs ameliorate multiple neurological disorders through anti\u2010inflammatory and anti\u2010apoptotic effects, increased cerebral blood flow, reduced excitotoxicity, decreased dendritic spine loss, reduced oxidative stress, and enhanced neurosteroid secretion. In animal models, sEH inhibition elevates endogenous EET bioavailability, slows progression of various central nervous system diseases, and attenuates brain injury. However, sEH inhibitor development faces several challenges, including species differences in CYP expression, insufficient blood\u2013brain barrier penetration, bleeding risks, failure of some candidates in late\u2010stage trials, and the limitations of single\u2010target inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>EETs are endogenous multifaceted neuroprotective mediators that act through convergent anti\u2010inflammatory, anti\u2010apoptotic, and vascular mechanisms. sEH inhibition represents a highly attractive yet challenging therapeutic strategy for a wide spectrum of central nervous system disorders. Future progress requires: development of brain\u2010penetrant or dual\u2010target sEH inhibitors; identification of EET\u2010specific G protein\u2010coupled receptors (GPCRs) and biomarkers for patient stratification; improved preclinical models that better translate to humans; and rigorous clinical evaluation to define safety and efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.71121","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:50:46Z","timestamp":1788929446000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Roles of\n                    <scp>EET<\/scp>\n                    s in Neurological Disorders"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4751-1365","authenticated-orcid":false,"given":"Rong","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Neurology Zhongshan Hospital 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