Study on sex-differential liver injury induced by acetaminophen and its molecular mechanism based on intestinal flora

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI), with gender-specific differences in susceptibility. However, the mechanism underlying this phenomenon remains unclear. Our study reveals that the gender-specific differences in susceptibility to APAP-induced hepatotoxicity are due to differences in the gut microbiota. Through microbial multi-omics and cultivation, we observed increased gut microbiota-derived deguelin content in both women and female mice. Administration of deguelin was capable of alleviating acute liver failure in APAP-treated male mice, and this protective effect was associated with the inhibition of hepatocyte ferroptosis. Transcriptomic analysis revealed that deguelin reduced the expression of thyrotropin receptor (Tshr) in hepatocytes with APAP treatment. Pharmacologic suppression of hepatic Tshr expression using ML224 significantly suppressed APAP-induced hepatocyte ferroptosis in male mice. These findings suggest that gut microbiota-derived deguelin plays a crucial role in reducing APAP-induced hepatotoxicity in female mice, offering new insights into therapeutic strategies for DILI.

对乙酰氨基酚（Acetaminophen, APAP）过量是药物性肝损伤（drug-induced liver injury, DILI）的主要致病原因之一，其易感性存在显著性别差异。然而，该现象背后的潜在机制仍未明确。本研究揭示，机体对APAP诱导的肝毒性的易感性性别差异，源于肠道菌群的差异。通过微生物多组学与培养组学分析，我们观察到女性及雌性小鼠体内肠道菌群衍生的鱼藤素（deguelin）含量均显著升高。向APAP造模的雄性小鼠施用鱼藤素，可有效缓解其急性肝衰竭，且该保护作用与抑制肝细胞铁死亡（ferroptosis）密切相关。转录组学分析显示，在APAP处理的肝细胞中，鱼藤素可降低促甲状腺激素受体（thyrotropin receptor, Tshr）的表达水平。使用ML224对肝脏Tshr表达进行药理学抑制，可显著抑制APAP诱导的雄性小鼠肝细胞铁死亡。上述研究结果表明，肠道菌群衍生的鱼藤素在减轻雌性小鼠APAP诱导的肝毒性过程中发挥关键作用，为药物性肝损伤的治疗策略提供了全新的研究视角。