Warner_2023_Am.J.Pathol__

Alcohol-associated liver disease (ALD) is a serious public health problem with limited pharmacological options. The goal of the current study was to investigate the efficacy of pharmacological inhibition of soluble epoxide hydrolase (sEH, an enzyme involved in lipid metabolism) in experimental ALD and to examine the underlying mechanisms. C57BL/6J male mice underwent acute-on-chronic ethanol (EtOH) feeding with or without the sEH inhibitor, TUCB. Liver injury was assessed by multiple end-points. Liver epoxy- and dihydroxy-fatty acids were measured by targeted metabolomics. Whole liver RNA sequencing was performed and free modified RNA bases were measured by mass spectrometry. EtOH-induced liver injury was ameliorated by TUCB treatment as evidenced by reduced plasma alanine aminotransferase levels, and was associated with attenuated alcohol-induced endoplasmic reticulum stress, reduced neutrophil infiltration, and increased numbers of hepatic M2 macrophages. TUCB altered liver epoxy- and dihydroxy-fatty acids and led to a unique hepatic transcriptional profile characterized by decreased expression of genes involved in apoptosis, inflammation, fibrosis, and carcinogenesis. Several modified RNA bases were robustly changed by TUCB, including m(6)A and ms(2)t(6)A. These findings demonstrated the beneficial effects of sEH inhibition by TUCB in experimental EtOH-induced liver injury, warranting further mechanistic studies to explore the underlying mechanisms, and highlighting the translational potential of sEH as a drug target for this disease.