PFOA/PFOS induce ferroptosis in bladder epithelial cells through inhibition of ACSL4 ubiquitination

Introduction Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants, but their role in bladder epithelial injury remains unclear. Methods SV-HUC-1 cells were exposed to PFOA and PFOS. Cell viability, lipid peroxidation, and ROS levels were assessed using CCK-8 assay, flow cytometry, and transmission electron microscopy. Protein expression and ubiquitination were analyzed by Western blotting and molecular docking. Results PFOA and PFOS induced ferroptosis in bladder epithelial cells, characterized by increased lipid peroxidation and ROS levels. Mechanistically, PFOA/PFOS inhibited ACSL4 ubiquitination at K593 and K690, leading to its stabilization and promoting ferroptosis. Knockdown of ACSL4 significantly reversed these effects. Discussion These findings reveal a novel mechanism by which PFAS induce ferroptosis via regulation of ACSL4 ubiquitination, providing new insights into PFAS-induced bladder toxicity.