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Targeting a specific pathway of polyunsaturated fatty acid (PUFA) metabolism, in which beneficial FA\u2010derived compounds, known as epoxy fatty acids (EpFAs), are rapidly converted into less active or inactive metabolites by the enzyme, soluble epoxide hydrolase (s\u2010EH), has shown promise in treating various pathological conditions. In this study, the s\u2010EH inhibitor,\n                      <jats:italic>t<\/jats:italic>\n                      \u2010TUCB, was tested for its efficacy in attenuating liver damage induced by chronic ethanol (EtOH) consumption in an animal model that mimics early\u2010stage ALD in humans.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      C57BL6\/J male mice were fed an EtOH\u2010containing diet with or without\n                      <jats:italic>t<\/jats:italic>\n                      \u2010TUCB for 8\u2009weeks. Liver steatosis, inflammation, and injury were evaluated. Fecal 16S rRNA sequencing was performed to examine the impact of s\u2010EH inhibition on the gut microbiota composition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      EtOH\u2010induced liver injury was attenuated in\n                      <jats:italic>t<\/jats:italic>\n                      \u2010TUCB\u2010treated mice, with a notable decrease in endoplasmic reticulum stress, hepatocyte cell death, and proinflammatory cytokine expression. There was no effect of\n                      <jats:italic>t<\/jats:italic>\n                      \u2010TUCB on EtOH\u2010induced hepatic steatosis.\n                      <jats:italic>t<\/jats:italic>\n                      \u2010TUCB treatment shifted the liver lipid profile, increasing several EpFAs, such as 17,18\u2010EpETE and 19,20\u2010EpDPA. These EpFAs decreased apoptosis and LPS\u2010induced expression of proinflammatory cytokines in\u00a0vitro.\n                      <jats:italic>t\u2010<\/jats:italic>\n                      TUCB treatment significantly increased\n                      <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                      , a species known for its beneficial properties, in control but not in EtOH\u2010fed mice. The EtOH\u2010induced increase in bacteria taxa previously associated with liver injury, including the\n                      <jats:italic>Peptostreptococcaceae<\/jats:italic>\n                      family and the species,\n                      <jats:italic>Alistipes massieliensis<\/jats:italic>\n                      , was reduced in\n                      <jats:italic>t<\/jats:italic>\n                      \u2010TUCB\u2010treated mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our data demonstrate the beneficial effects of\n                      <jats:italic>t<\/jats:italic>\n                      \u2010TUCB treatment on chronic EtOH\u2010induced liver injury and gut microbiota imbalances, in turn, promoting liver health. These findings suggest that pharmacologic s\u2010EH inhibition may serve as a promising strategy for reducing liver injury in ALD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/acer.70109","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:10:40Z","timestamp":1751587840000},"page":"1730-1743","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effects of soluble epoxide hydrolase inhibition on liver injury and gut microbiota in mice chronically fed ethanol"],"prefix":"10.1111","volume":"49","author":[{"given":"Dennis R.","family":"Warner","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine University of Louisville  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2022-7854","authenticated-orcid":false,"given":"Jeffrey B.","family":"Warner","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine University of Louisville  Louisville Kentucky USA"},{"name":"Department of Pharmacology and Toxicology, School of Medicine University of Louisville  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmeen","family":"Abdelfadil","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine University of Louisville  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josiah E.","family":"Hardesty","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine University of Louisville  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Treves","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine University of Louisville  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Lei","sequence":"additional","affiliation":[{"name":"Division of Immunotherapy, Department of Surgery, School of Medicine University of Louisville  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah E.","family":"Hanford","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine University of Louisville  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7219-8939","authenticated-orcid":false,"given":"Craig J.","family":"McClain","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine University of Louisville  Louisville Kentucky USA"},{"name":"Department of Pharmacology and Toxicology, School of Medicine University of Louisville  Louisville Kentucky USA"},{"name":"Alcohol Research Center University of Louisville  Louisville Kentucky USA"},{"name":"Hepatobiology and Toxicology Center, School of Medicine University of Louisville  Louisville Kentucky USA"},{"name":"Robley Rex Veterans Affairs Medical Center  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9545-6451","authenticated-orcid":false,"given":"Irina A.","family":"Kirpich","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine University of Louisville  Louisville Kentucky USA"},{"name":"Alcohol Research Center University of Louisville  Louisville Kentucky USA"},{"name":"Hepatobiology and Toxicology Center, School of Medicine University of Louisville  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16009"},{"key":"e_1_2_9_3_1","unstructured":"Adler D. 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