Polystyrene Microplastics Induced Hepatocytes Pyroptosis, Apoptosis and Ferroptosis via GSDMD-N-Mediated Mitochondrial Damage

Microplastics (MPs), as emerging food contaminants, have been established to exert adverse effects on the liver. However, the precise toxicological mechanisms remain elusive. Our results demonstrated that MPs triggered mitochondrial dysfunction and mitochondrial ROS (mtROS) accumulation, which subsequently activated NLRP3/Caspase-1/GSDMD-N-dependent Pyroptosis in hepatocytes. Notably, beyond its canonical translocation to the plasma membrane, GSDMD-N was observed to form pores on the mitochondrial outer membrane, exacerbating mitochondrial damage. The mitochondrial GSDMD-N pores amplified mtROS overproduction, triggering lysosomal membrane permeabilization (LMP) and facilitating lysosomal iron efflux, which ultimately initiated Ferroptosis. Concurrently, mitochondrial GSDMD-N mediated mitochondrial intrinsic Apoptosis by promoting cytochrome c release and Caspase-3 activation. Collectively, our findings revealed that MPs induced GSDMD-N activation and its mitochondrial translocation, which in turn initiated Pyroptosis, Ferroptosis, and Apoptosis in hepatocytes. This study provided novel mechanistic insights into MPs-induced hepatotoxicity, identifying GSDMD-N as a potential central hub coordinating multiple cell death modalities.