Hexafluoropropylene oxide trimer acid exposure triggers necroptosis and inflammation through the Wnt/β-catenin/NF-κB axis in the liver

Hexafluoropropylene oxide trimer acid (HFPO-TA), an emerging alternative to perfluorooctanoic acid (PFOA), has recently been identified as a significant environmental pollutant. Nevertheless, there is a scarcity of studies regarding the hepatotoxic effects of HFPO-TA. Here, we investigated the types and potential mechanisms of liver damage caused by HFPO-TA. Initially, we validated that the introduction of HFPO-TA resulted in the Wnt/β-catenin signaling (W/β signaling) activation, as well as the induction of necroptosis and inflammation, both in the liver of mice and in HepG2 cells. Subsequently, we established that the W/β signaling mediated the necroptosis and inflammation observed in the liver and HepG2 cells exposed to HFPO-TA. Finally, we demonstrated that the phosphorylated form of NF-κB p65 (p-NF-κB p65) played a role in mediating the necroptosis and inflammation, and its activity could be regulated by the W/β signaling pathway in the liver of mice and HepG2 cells exposed to HFPO-TA. In conclusion, our investigation elucidates the role of HFPO-TA in inducing necroptosis and inflammation in the liver, which is facilitated through the activation of the W/β/NF-κB axis.