Tris(1,3-dichloro-2-propyl) phosphate induces hepatic injury and lipid metabolic disturbance associated with ferroptosis: Evidence from mice and human liver organoids.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a widely used organophosphate flame retardant that is ubiquitously detected in environmental matrices and human biological samples, raising concerns about its potential health risks. However, the mechanisms underlying TDCPP-induced hepatotoxicity remain incompletely understood. Here, we investigated the hepatic effects of TDCPP using an integrated in vivo-in vitro approach combining a mouse exposure model, human-derived 3D liver organoids, and network toxicology analysis. Sub-chronic oral exposure to TDCPP in mice induced evident liver injury, characterized by histopathological alterations, elevated serum aminotransferase activities, and hepatic triglyceride accumulation accompanied by systemic lipid metabolism disorders. TDCPP exposure also disrupted hepatic redox homeostasis, as evidenced by glutathione depletion, enhanced lipid peroxidation, and downregulation of glutathione peroxidase 4, a key suppressor of ferroptosis. Consistently, TDCPP exposure reduced cell viability, promoted lipid droplet accumulation, increased reactive oxygen species levels, and suppressed GPX4 expression in human 3D liver organoids, recapitulating the major pathological features observed in vivo. Network toxicology analysis identified peroxisome proliferator-activated receptor gamma (PPARG) as a central node potentially involved in TDCPP-induced hepatotoxicity and ferroptosis, which was further supported by molecular docking analysis. Experimental validation confirmed that TDCPP exposure significantly upregulated PPARG expression in both mouse liver tissues and liver organoids. Overall, these findings indicate that TDCPP induces hepatic injury and lipid metabolic disturbance in association with ferroptosis, potentially mediated through a PPARG-GPX4 regulatory axis, providing human-relevant mechanistic insight into the hepatotoxic risk of this environmental contaminant.