Bisphenol A induces lysosomal-dependent cell death in hepatocytes via mitochondrial ROS-mediated lysosomal membrane permeabilization

Abstract Bisphenol A (BPA), an organic compound widely found in food packaging materials, is inevitably released into the food and beverages. BPA has been confirmed to be hepatotoxic, however, the precise mechanism remains unclear. In this study, we demonstrated that lysosomal membrane permeabilization (LMP) mediates BPA-induced liver injury. Further mechanistic investigation revealed that BPA resulted in cathepsin B (CTSB) release and iron efflux by triggering LMP, ultimately inducing lysosomal-dependent pyroptosis and ferroptosis. Furthermore, mitochondrial reactive oxygen species (mtROS) were identified as the trigger for BPA-induced LMP. BPA elicited mtROS overproduction by disrupting mitochondrial quality control, thereby inducing LMP. In conclusion, we demonstrated that BPA caused CTSB release and lysosomal iron efflux via the mtROS-mediated LMP, which ultimately resulted in pyroptosis and ferroptosis. Our study revealed that the mtROS/LMP axis may be a common pathway for lysosomal-dependent pyroptosis and ferroptosis, providing novel mechanistic insights into BPA-induced hepatotoxicity.