Role of NOX4 and GSH in Cadmium-Induced Renal Redox Homeostatic Dysregulation of Rats and APO Intervention Effect Study.

This study aimed to investigate the roles and mechanisms of NADPH oxidase 4 (NOX4) and glutathione (GSH) in cadmium (Cd)-induced renal oxidative stress and to evaluate the protective effect of apocynin (APO). A rat model of Cd-induced renal injury was established and treated with APO to explore the interactions between NOX4 and GSH in redox imbalance. And a NOX4 knockdown model was constructed in NRK-52E cells to further elucidate the regulatory role of NOX4 in Cd-mediated nephrotoxicity. Cd exposure caused significant renal tubular epithelial cell injury, manifested as histopathological changes, increased serum creatinine and urea levels, and elevated oxidative stress markers. In addition, Cd markedly upregulated NOX4 expression, enhanced reactive oxygen species (ROS) production, and reduced intracellular GSH levels. This imbalance in redox homeostasis was accompanied by increased pro-inflammatory cytokine release and mitochondrial dysfunction. APO treatment significantly alleviated renal tissue damage, suppressed NOX4 expression, reduced ROS accumulation and restored GSH content. In vitro experiments found that NOX4 knockdown in NRK-52E cells attenuated Cd-induced ROS production, which could preserve antioxidant enzyme activity and protect cells from apoptosis. NOX4 activation and GSH depletion are pivotal mechanisms in Cd-induced nephrotoxicity. APO exerts protective effects by inhibiting NOX4-dependent ROS production, restoring redox homeostasis, and improving renal function. These findings provide mechanistic insights into Cd toxicity and highlight NOX4 as a potential therapeutic target for Cd-associated kidney injury. The online version contains supplementary material available at 10.1007/s12011-026-05021-9.