2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) triggers Z-DNA-binding protein 1(ZBP1)- (Receptor-interacting serine/threonine-protein kinase 3) RIP3 mediated programmed necrosis in hepatic cells by inducing mitochondrial left-handed helix (Z-DNA) release

Traditional Polybrominated Diphenyl Ethers (PBDEs) have been gradually banned due to their significant health impacts. As a substitute, the novel brominated flame retardant 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) has been extensively utilized in industrial and consumer products. TBB has been detected in various environmental media, organisms, and humans, suggesting potential health risks. However, existing toxicological studies on TBB are still limited. The liver is one of the most important target organs in toxicological research. Therefore, we explored the toxicological effects of TBB on liver. Therefore, a series of corresponding biochemical experiments were conducted to evaluate the toxicological effects of TBB. Firstly, CCK8 and EdU assays indicated that TBB blocked the proliferation of hepatocytes. Cell cycle analysis demonstrated that TBB inhibited cell cycle progression; Secondly, TBB treatment causes mitochondrial damage by detection of mitochondrial membrane potential. Further work found that TBB led to programmed necrosis, which is mediated by ZBP1. Mechanistically, we found that TBB induced mitochondrial damage, as evidenced by impaired mitochondrial membrane potential, followed by mitochondrial genome instability and subsequent generation/release of mitochondrial Z-DNA, which subsequently drives both cell death and inflammatory responses. In conclusion, this study investigated the toxicological effects of the novel brominated flame retardant (TBB), these findings indicate that limiting TBB usage should be prioritized in future studies.