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The inhibition of soluble epoxide hydrolase (s-EH) has emerged as a promising therapeutic strategy in experimental ALD. In this study, we developed a novel liver-targeted formulation of the s-EH inhibitor t-TUCB, encapsulated in fusogenic lipid vesicles (FLVs), and tested its therapeutic efficacy in a mouse model of ALD. This formulation achieved high encapsulation efficiency and targeted primarily hepatocytes. Male C57BL\/6J mice were fed an ethanol-containing liquid diet for 10 days, followed by a single ethanol binge on day 11. A subset of mice received a single intraperitoneal dose of t-TUCB-FLVs two hours before the binge. t-TUCB-FLVs significantly attenuated liver injury as assessed by multiple endpoints, including decreased plasma ALT levels and hepatocyte cell death. Spatial transcriptomic analysis revealed that t-TUCB-FLV treatment modulated gene expression in hepatocytes across multiple key pathways, including xenobiotic metabolism, carbohydrate and lipid metabolism, bile acid homeostasis, inflammation, energy balance, and circadian rhythm. Collectively, these findings support liver-specific s-EH inhibition as a potentially effective therapeutic approach for ALD.<\/jats:p>","DOI":"10.3390\/biology14091267","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T07:56:51Z","timestamp":1757923011000},"page":"1267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte-Specific Transcriptional Responses to Liver-Targeted Delivery of a Soluble Epoxide Hydrolase Inhibitor in a Mouse Model of Alcohol-Associated Liver Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Dennis R.","family":"Warner","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY 40202, 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, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1955-3046","authenticated-orcid":false,"given":"Josiah E.","family":"Hardesty","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmeen","family":"Abdelfadil","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chirag","family":"Soni","sequence":"additional","affiliation":[{"name":"Endo ProTech, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Bauer","sequence":"additional","affiliation":[{"name":"Endo ProTech, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Maldonado","sequence":"additional","affiliation":[{"name":"Endo ProTech, Louisville, KY 40202, USA"},{"name":"Department of Physiology, University of Louisville, Louisville, KY 40202, 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, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"University of Louisville Alcohol Center, University of Louisville, Louisville, KY 40202, USA"},{"name":"University of Louisville Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA"},{"name":"Robley Rex Veterans Medical Center, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina A.","family":"Kirpich","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA"},{"name":"University of Louisville Alcohol Center, University of Louisville, Louisville, KY 40202, USA"},{"name":"University of Louisville Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"332","DOI":"10.4254\/wjh.v12.i7.332","article-title":"Oxidative stress in alcohol-related liver disease","volume":"12","author":"Tan","year":"2020","journal-title":"World J. 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