FXR as a pivotal role linking JNK and G0s2 mitigates triptolide-induced hepatotoxicity through the regulation of metabolic disorder of liver
Triptolide, often abbreviated as TP, is a primary bioactive compound extracted from the plant Tripterygium wilfordii Hook.1 f. This compound has demonstrated significant anti-tumor, anti-inflammatory, and immunomodulatory effects. However, its clinical use is limited by serious adverse reactions, particularly hepatotoxicity, or liver damage.2 To investigate this liver toxicity, our study employed intraperitoneal injection to establish a model of TP-induced hepatotoxicity, characterized by increased levels of liver enzymes known as transaminases, specifically aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as metabolic disorders.
We found that the administration of SP600125, an inhibitor of the c-Jun N-terminal kinase (JNK) signaling pathway, effectively reduced the elevated transaminase levels and inflammation caused by TP. However, the ability of SP600125 to counteract the metabolic disturbances induced by TP was dependent on the presence of the Farnesoid X receptor (Fxr), as demonstrated in experiments using Fxr knockout mice, which lack the Fxr gene.
Supplementation with GW4064, a known Fxr agonist or activator, restored the concentrations of bile acids, long-chain fatty acids, and carnitine that were disrupted by TP administration. Analysis of transcriptomic data revealed that G0/G1 switch gene 2 (G0s2) was among the genes most significantly affected by TP. Notably, the beneficial effects of both SP600125 and GW4064 were associated with an upregulation of G0s2 expression. In vitro experiments using small interfering RNA (siRNA) to reduce G0s2 expression showed that disrupting G0s2 intensified the cytotoxic effects of TP.
A comparative analysis of TP’s impact on the G0s2 gene in two mouse models, wild-type mice and Fxr knockout mice, showed a smaller reduction of G0s2 in wild-type mice compared to the Fxr knockout mice. This suggests that Fxr plays a role in mitigating the inhibitory effect of TP on G0s2. Taken together, Tanzisertib our findings indicate that aberrant signaling involving the JNK pathway, Fxr, and G0s2 plays a crucial role in the development of TP-induced hepatotoxicity. Therefore, targeting Fxr may represent a potential therapeutic strategy for alleviating the liver toxicity associated with triptolide.