To investigate APAP-induced sex-differential liver injury 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 pretreated with APAP. 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.