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Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus\u2013induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and in the murine heart and correlated with the increased expression and activity of sEH after coxsackie B3 virus infection. Administration of a sEH inhibitor prevented coxsackie B3 virus\u2013induced cardiac dysfunction and inflammatory infiltration. Importantly, EET\/sEH inhibitor treatment attenuated viral infection or improved viral resistance by activating type I IFN (interferon) signaling. At the molecular level, EETs enhanced the interaction between GSK3\u03b2 (glycogen synthase kinase-3 beta) and TBK1 (TANK-binding kinase 1) to promote IFN-\u03b2 production. Our findings revealed that EETs and sEH inhibitors prevent the progress of coxsackie B3 virus\u2013induced myocarditis, particularly by promoting viral resistance by increasing IFN production.<\/jats:p>","DOI":"10.1161\/circresaha.123.322619","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T09:00:19Z","timestamp":1694163619000},"page":"772-788","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Epoxyeicosatrienoic Acids Prevent Cardiac Dysfunction in Viral Myocarditis via Interferon Type I Signaling"],"prefix":"10.1161","volume":"133","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6259-9106","authenticated-orcid":true,"given":"Zhou","family":"Zhou","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Tongji Hospital (Z.Z., M.Z., C.Z., X.G., Z.W., J.W., C.C., D.W.W.), Tongji Medical College, Huazhong University of Science and 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