Hepatocyte-Specific Transcriptional Responses to Liver-Targeted Delivery of a Soluble Epoxide Hydrolase Inhibitor in a Mouse Model of Alcohol-Associated Liver Disease

Alcohol-associated liver disease (ALD) is a chronic condition caused by excessive alcohol consumption, with limited effective pharmacological treatments currently available. 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 <i>t</i>-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 <i>t</i>-TUCB-FLVs two hours before the binge. <i>t</i>-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 <i>t</i>-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.