Aflatoxin B1 Induces Pyroptosis and Apoptosis in Renal Cells by Mediating Mitophagy Dysfunction and Mitochondrial Pore Formation

Aflatoxin B1 (AFB1), a potent mycotoxin, induces nephrotoxicity through previously unrecognized crosstalk between pyroptosis and apoptosis. Using in vivo and in vitro renal injury models, we demonstrate that AFB1 impairs mitophagy, leading to an excessive level of reactive oxygen species (ROS) accumulation. This ROS surge triggers lysosomal membrane permeabilization (LMP) and cathepsin B (CTSB)-dependent activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, initiating caspase-1–mediated pyroptosis via gasdermin D N-terminal (GSDMD-N) pore formation. Importantly, AFB1 also induces cardiolipin translocation to the mitochondrial outer membrane, where pyroptosis-derived GSDMD-N is recruited to form mitochondrial pores. This results in cytochrome c (Cyt-c) release and activation of a caspase-dependent noncanonical apoptotic cascade distinct from the classical apoptotic pathway. These findings establish GSDMD-N-mediated mitochondrial damage as a molecular bridge linking pyroptosis to apoptosis in AFB1 nephrotoxicity and highlight GSDMD-N inhibition as a promising therapeutic strategy. Given AFB1’s persistence and bioaccumulation in the food chain, these mechanistic insights provide a molecular basis for developing targeted interventions to mitigate its health risks in agricultural production and food safety.