Intestinal deguelin drives resistance to acetaminophen-induced hepatotoxicity in female mice
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.
Authors
- Zhenhua Zeng (ORCID: https://orcid.org/0000-0002-9509-1536)
- Lei Gao (ORCID: https://orcid.org/0000-0001-9030-390X)
- Yunong Zeng
- Xintao Huang (ORCID: https://orcid.org/0000-0002-9683-9518)
- Zhibin Zhao (ORCID: https://orcid.org/0000-0002-8994-3106)
- Weidong Xiao (ORCID: https://orcid.org/0000-0002-9300-980X)
- Hong Yang (ORCID: https://orcid.org/0000-0003-0869-3369)
- Zhichao Yu (ORCID: https://orcid.org/0000-0001-5123-9191)
- Ping Qin (ORCID: https://orcid.org/0000-0001-6741-6228)
- Shenhai Gong (ORCID: https://orcid.org/0000-0002-1366-6894)
- Yi He (ORCID: https://orcid.org/0000-0002-9367-6186)
- Lei Li (ORCID: https://orcid.org/0000-0001-9910-5600)
- Ze Wang (ORCID: https://orcid.org/0000-0002-8339-5567)
- Shumin Cai
- Yanru Li (ORCID: https://orcid.org/0000-0002-8529-8744)
- Peiheng Guo
- Xiaoshan Zhao
- Hongbin Hu
- Rong Wu (ORCID: https://orcid.org/0009-0008-0583-7463)
Institutions
- Army Medical University (CN)
- Third Affiliated Hospital of Southern Medical University (CN)
- Nanfang Hospital (CN)
- Xinqiao Hospital (CN)
- Guangdong Provincial People's Hospital (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Southern Medical University (CN)
- Army Medical College (PK)
Publication Details
- Journal
- Gut Microbes
- Published
- 2024-09-21
- DOI
- https://doi.org/10.1080/19490976.2024.2404138
- Citations
- 4
- Primary Topic
- Drug-Induced Hepatotoxicity and Protection
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province