Inhibition of Nrf2 Activity in Mitigating Cadmium-Induced Mitochondrial Damage and Pyroptosis

Acute cadmium (Cd) exposure induces hepatic toxicity in murine models, where oxidative stress and subsequent inflammatory responses are recognized as principal contributors to hepatocyte damage. The NLRP3 inflammasome, a pivotal member of the NOD-like receptor family, mediates pyroptotic cell death in diverse hepatic inflammatory pathologies. While murine liver exhibits heightened susceptibility to heavy metal toxicity, the mechanistic basis of Cd-induced hepatocyte injury remains incompletely characterized. This study aims to clarify the cytotoxic effects of Cd on murine hepatocyte line BNL CL.2 and systematically dissect the underlying molecular mechanisms. Via molecular and cellular assays, we evaluated mitochondrial function, reactive oxygen species (ROS) levels, NLRP3 inflammasome activation, and pyroptotic features in BNL CL.2 cells post Cd exposure; intervened with ROS scavengers N-acetylcysteine (NAC) and Mito-TEMPO, and detected transcriptional activity of the antioxidant regulator Nrf2. Experimental data demonstrate that Cd exposure triggers mitochondrial dysfunction coupled with excessive ROS production, concomitant NLRP3 inflammasome activation, and characteristic plasma membrane rupture confirming pyroptosis. Notably, NAC and Mito-TEMPO effectively attenuate these pathological responses, establishing ROS as critical regulators of Cd-induced NLRP3 inflammasome activation; mechanistically, Cd suppresses Nrf2 transcriptional activity and downstream antioxidant gene expression, thereby disrupting redox homeostasis. These findings collectively delineate a pathogenic cascade where Cd impairs mitochondrial integrity and disrupts Nrf2-dependent antioxidant defenses, synergistically driving ROS-mediated NLRP3 inflammasome activation and subsequent hepatocyte pyroptosis. This mechanism provides novel insights into heavy metal hepatotoxicity and identifies potential targets for treating Cd-induced liver injury.