Triclocarban drives intrahepatic cholangiocyte injury by triggering ferroptosis via the SLC7A11/GSH/GPX4 axis.

Triclosan (TCS) and triclocarban (TCC), which are widely used as antimicrobial agents, come into direct contact with humans due to their increasing environmental release. Because of concerns regarding the environmental impact and potential hepatotoxicity of TCS, it is being phased out in many countries and substituted with TCC. However, the biological and molecular mechanisms underlying TCC's toxicity, particularly in relation to liver damage, remain largely unexplored. In this study, we demonstrated that although TCC exhibited reduced hepatotoxicity relative to TCS, it exerted a more significant impact on cholangiocytes compared to TCS. Using an intrahepatic cholangiocyte organoid model, we identified ferroptosis as a predominant pathological feature of TCC-induced cytotoxicity and dysfunction in cholangiocytes, characterized by iron overload, ROS generation, lipid peroxidation, and aberrant activation of the ferroptosis pathway. Mechanistically, TCC not only elevated Fe2+ levels in organoids by disrupting iron metabolism pathway but also impaired the antioxidant system by targeting the SLC7A11/GSH/GPX4 antioxidant axis, indicating that TCC induced ferroptosis through both canonical and noncanonical pathways. Notably, targeting ferroptosis with the ferroptosis inhibitor Fer-1 effectively rescued the cytotoxicity and attenuated the enhanced secretory function of organoids induced by TCC. Our study elucidates the critical cellular events occurring in cholangiocytes exposed to TCC and provides valuable insights into the mechanisms by which TCC exerts its toxic effects within the hepatobiliary system.