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Several laboratories demonstrated that 20\u2010HETE synthesis inhibition reduces infarct volume following middle cerebral artery occlusion (MCAO) in male animals. Here, we investigated whether neuroprotection with the 20\u2010HETE synthesis inhibitor HET0016 administered after transient MCAO in rats differs by sex and whether ischemia differentially induces\n                    <jats:italic>Cyp4a<\/jats:italic>\n                    genes in a sex\u2010dependent manner. HET0016 significantly improved sensorimotor performance and reduced infarct volume compared to vehicle treatment in males. However, these improvements were less consistent in females.\n                    <jats:italic>Cyp4a2<\/jats:italic>\n                    and\n                    <jats:italic>Cyp4a3<\/jats:italic>\n                    genes were detected at similar levels in brain tissue from male and female rats undergoing sham surgery or MCAO\/reperfusion. Interestingly, the\n                    <jats:italic>Cyp4a8<\/jats:italic>\n                    gene was detectable in intact and castrated males and increased 3\u20104\u2010fold after MCAO. In contrast,\n                    <jats:italic>Cyp4a8<\/jats:italic>\n                    was undetectable in brains of intact or ovariectomized female rats. Oxygen\u2013glucose deprivation in cultured murine neurons revealed male\u2010selective induction of the homolog gene\n                    <jats:italic>Cyp4a12a<\/jats:italic>\n                    , the knockdown of which blocked the increase in 20\u2010HETE. These results indicate that innate male\u2010selective\n                    <jats:italic>Cyp4a<\/jats:italic>\n                    gene induction and 20\u2010HETE signaling are significant factors that can contribute to sex differences in the outcomes from ischemic stroke.\n                  <\/jats:p>","DOI":"10.14814\/phy2.70762","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T05:44:06Z","timestamp":1770183846000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex\u2010dependent role of 20\u2010\n                    <scp>HETE<\/scp>\n                    synthesis in outcome from ischemic stroke in rats"],"prefix":"10.14814","volume":"14","author":[{"given":"Rongrong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University  Baltimore Maryland USA"},{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanrong","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suyi","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5890-9992","authenticated-orcid":false,"given":"Raymond C.","family":"Koehler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeng\u2010Jin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"issue":"19","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"7543","DOI":"10.1523\/JNEUROSCI.21-19-07543.2001","article-title":"Estrogen and Bcl\u20102: Gene induction and effect of transgene in experimental stroke","volume":"21","author":"Alkayed N. 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