Intestinal deguelin drives resistance to acetaminophen-induced hepatotoxicity in female mice
Shenhai Gong,
Yunong Zeng,
Ze Wang,
Yanru Li,
Rong Wu,
Lei Li,
Hongbin Hu,
Ping Qin,
Zhichao Yu,
Xintao Huang,
Peiheng Guo,
Hong Yang,
Yi He,
Zhibin Zhao,
Weidong Xiao,
Xiaoshan Zhao,
Lei Gao,
Shumin Cai,
Zhenhua Zeng
Affiliations
Shenhai Gong
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
Yunong Zeng
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
Ze Wang
Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
Yanru Li
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
Rong Wu
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
Lei Li
Henan Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine and Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Hongbin Hu
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
Ping Qin
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
Zhichao Yu
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
Xintao Huang
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
Peiheng Guo
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
Hong Yang
Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
Yi He
Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
Zhibin Zhao
Medical Research Institute, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, China
Weidong Xiao
Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China
Xiaoshan Zhao
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
Lei Gao
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
Shumin Cai
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
Zhenhua Zeng
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
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 hepatotoxicity in APAP-treated male mice, and this protective effect was associated with the inhibition of hepatocyte oxidative stress. Mechanistically, deguelin reduced the expression of thyrotropin receptor (TSHR) in hepatocytes with APAP treatment through direct interaction. Pharmacologic suppression of TSHR expression using ML224 significantly increased hepatic glutathione (GSH) in APAP-treated 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.
