Aflatoxin B1 Induces Pyroptosis and Apoptosis in Renal Cells by Mediating Mitophagy Dysfunction and Mitochondrial Pore Formation
Xinyu Yao, Min Gao, Jing Lu, Xuming Deng, Shuang Guan
Abstract
Aflatoxin B 1 (AFB 1 ), 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 AFB 1 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, AFB 1 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 AFB 1 nephrotoxicity and highlight GSDMD-N inhibition as a promising therapeutic strategy. Given AFB 1 ’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.