Liver RNASeq data from experimental mice fed ethanol with or without TUCB treatment.. Hepatic Transcriptome and Its Regulation Following Soluble Epoxide Hydrolase Inhibition in Alcohol-Associated Liver Disease

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 m6A and ms2t6A. 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.

酒精相关性肝病（Alcohol-associated liver disease, ALD）是一类严重的公共卫生问题，目前可供选择的药物治疗手段十分有限。本研究旨在探讨可溶性环氧化物水解酶（soluble epoxide hydrolase, sEH，一种参与脂质代谢的酶）的药物抑制策略在实验性酒精相关性肝病中的疗效，并解析其潜在作用机制。研究选用C57BL/6J品系雄性小鼠，分别开展慢性叠加急性乙醇（ethanol, EtOH）喂养实验，并设置是否联合sEH抑制剂TUCB的对照分组。通过多终点指标评估小鼠肝脏损伤程度；采用靶向代谢组学检测肝脏内环氧脂肪酸与二羟基脂肪酸的水平；完成全肝RNA测序，并借助质谱法检测游离修饰RNA碱基的表达变化。结果显示，TUCB治疗可有效缓解乙醇诱导的肝脏损伤：血浆丙氨酸氨基转移酶水平显著降低，同时伴随乙醇诱导的内质网应激减弱、中性粒细胞浸润减少以及肝脏M2巨噬细胞数量增加。TUCB可调控肝脏内环氧脂肪酸与二羟基脂肪酸的代谢谱，并塑造出独特的肝脏转录特征，具体表现为凋亡、炎症、纤维化及癌变相关基因的表达下调。此外，TUCB可显著改变多种修饰RNA碱基的水平，包括m6A与ms2t6A。本研究证实了sEH抑制剂TUCB在实验性乙醇诱导肝损伤中的保护作用，为进一步解析其潜在分子机制提供了研究方向，同时凸显了sEH作为该疾病药物靶点的转化应用潜力。