Targeting TBXAS1: a novel target of daidzein in alleviating APAP-induced hepatic injury

Background and Purpose Acetaminophen (APAP) overdose is a major cause of acute liver failure. TBXAS1, driving inflammation via processes like inflammatory cell aggregation, vasoconstriction, and thrombosis, was picked out as a crucial inflammatory regulator that catalyzes thromboxane A2 generation. This study was conducted to explore whether Daidzein (DAI), a bioactive compound, has hepatoprotective effects against APAP-induced liver injury by acting on TBXAS1. Methods and Results In vitro and in vivo experiments revealed that hepatic TBXAS1 levels increased following APAP induction. SiRNA-mediated TBXAS1 knockdown reduced APAP-induced inflammation and cytotoxicity. Network pharmacology and transcriptomic analysis identified TBXAS1 as a potential DAI target. In vivo, DAI pretreatment mitigated APAP-induced liver injury in mice and lowered TBXAS1 levels. In vitro, DAI pretreatment followed by APAP exposure in AML-12 cells resulted in reduced TBXAS1 expression and decreased inflammation, oxidative stress, and apoptosis. Mechanistic analysis showed that DAI regulates TBXAS1 expression both in vitro and in vivo. Specifically, DAI modulates the TLR4/NF-κB pathway by altering TXA2 levels mediated by TBXAS1, thereby protecting against APAP-induced injury. Conclusion TBXAS1 is identified as a novel target of DAI. By modulating TBXAS1, DAI can reduce APAP-induced liver damage, including hepatocyte injury, oxidative stress, apoptosis, and inflammation. This study provides a new therapeutic approach for managing APAP-induced liver damage.