2. Academic Validation
  3. FXR as a pivotal role linking JNK and G0s2 mitigates triptolide-induced hepatotoxicity through the regulation of metabolic disorder of liver

FXR as a pivotal role linking JNK and G0s2 mitigates triptolide-induced hepatotoxicity through the regulation of metabolic disorder of liver

  • Pharmacol Res. 2025 Jun:216:107738. doi: 10.1016/j.phrs.2025.107738.
Qinmei Li 1,  Jianfeng Huang 2,  Qi Zhao 3,  Fei Li 4
Affiliations

Affiliations

  • 1 Department of Pharmacy and Laboratory of Hepato-Intestinal Diseases and Metabolism, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; Shanwei Institute for Food and Drug Control, Shanwei, Guangdong Province 516622, China.
  • 3 Department of Pharmacy and Laboratory of Hepato-Intestinal Diseases and Metabolism, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 Department of Pharmacy and Laboratory of Hepato-Intestinal Diseases and Metabolism, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: feili@wchscu.cn.
PMID: 40288593 DOI: 10.1016/j.phrs.2025.107738
Abstract

Triptolide (TP), as a principal bioactive compound derived from Tripterygium wilfordii Hook. f., exhibits significant anti-tumor, anti-inflammatory, and immunomodulatory properties. However, the serious adverse reactions and hepatotoxicity of TP limit its clinical application. Therefore, in this study, an intraperitoneal injection was employed to establish a TP-induced hepatotoxicity model, characterized by elevated levels of transaminases (AST and ALT) and metabolic disorders. The administration of the JNK Inhibitor SP600125 effectively mitigated the elevated transaminases and inflammation induced by TP. The resistance of SP600125 to metabolic disturbances induced by TP was contingent upon FXR, as demonstrated through the use of FXR knockout mice. Supplementation of GW4064 restored the concentrations of bile acids, long-chain fatty acids, and carnitine disrupted by TP. Transcriptomic data suggested that G0s2 was one of the genes most severely disrupted by TP, and the ameliorative effects of SP600125 and GW4064 were accompanied by the upregulation of G0s2. The expression of G0s2 was disrupted by siRNA in vitro, thereby intensifying the cytotoxicity of TP. A comparative analysis of the impact of TP on the G0s2 gene in two mouse models revealed that a smaller reduction in wild-type mice compared to FXR-/- mice, indicating that FXR mitigates the inhibitory effect of TP on G0s2. The aberrant JNK/FXR/G0s2 signaling plays a key role in TP-induced hepatotoxicity. Targeting FXR might be a potential strategy for alleviating the liver toxicity of TP.

Keywords

Acetonitrile ( PubChem CID:6342); Chlorpropamide (PubChem CID:2727); Concanavalin A (PubChem CID:155486958); Dimethyl sulfoxide (PubChem CID:679); Ethanol (PubChem CID:702); Formic acid (PubChem CID:284); Fxr; G0s2; GW4064 (PubChem CID:9893571); Hepatotoxicity; JNK; Liver metabolism; Obeticholic Acid (PubChem CID:447715); SP600125 (PubChem CID:8515); Sunitinib (PubChem CID:5329102); Triptolide; Triptolide (PubChem CID:107985); Tween 80(PubChem CID:443315).

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