TCDCA inhibits pyroptosis to alleviate sepsis-related acute Hepatic injury via activating TGR5

Sepsis-related acute hepatic injury is a life - threatening complication in septic patients, and current treatments have limited efficacy. This study investigated the role of taurochenodeoxycholic acid in SALI using a cecal ligation and puncture mouse model. TCDCA treatment significantly reduced serum levels of liver injury markers, suppressed pro - inflammatory cytokines, and alleviated histological damage, including lobular disruption, inflammation, and hemorrhage. TCDCA also decreased hepatocyte apoptosis and modulated the liver macrophage response. Molecular docking showed a strong interaction between TCDCA and G protein - coupled bile acid receptor 1, and the TGR5 antagonist SBI-115 abolished TCDCA protective effects. Transcriptomic analysis identified 430 differentially expressed genes after TCDCA treatment, with enrichment in pyroptosis - related pathways. Western blot analysis confirmed that TCDCA inhibited the activation of NLRP3 inflammasome and downstream pyroptotic proteins, an effect reversed by SBI - 115. These results indicate that TCDCA protects against SALI by suppressing hepatocyte pyroptosis via TGR5. While these findings highlight TCDCA as a potential therapeutic for SALI, further research, including clinical trials, is needed to address species - specific differences and fully elucidate its mechanisms of action.