Ferroptosis in podocyte injury in diabetic kidney disease: mechanisms and therapeutic perspectives

Diabetic kidney disease (DKD) is a common and serious complication of diabetes and a major cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. Podocyte injury and loss are pathological hallmarks of DKD, and ferroptosis may contribute to disease progression. Ferroptosis is an iron-dependent form of regulated cell death characterized by membrane lipid peroxidation and has been implicated in DKD. Oxidative stress arises from an imbalance between oxidant and antioxidant systems, leading to the accumulation of reactive oxygen species (ROS) and potentially contributing to ferroptosis initiation. In DKD, hyperglycemia and dyslipidemia can disrupt redox homeostasis in podocytes, promote iron accumulation, and increase membrane lipid peroxidation. When membrane lipid peroxide accumulation exceeds the detoxification capacity of cellular antioxidant systems, podocyte ferroptosis may occur, disrupting the glomerular filtration barrier and promoting proteinuria and DKD progression. Restoring antioxidant defenses in podocytes or inhibiting iron-dependent membrane lipid peroxidation may represent potential therapeutic strategies for alleviating podocyte injury and slowing DKD progression. However, whether these approaches provide benefits beyond standard glycemic and blood pressure control remains to be determined in clinical studies. Direct evidence for podocyte ferroptosis currently comes primarily from in vitro and animal studies, and its cell-specific mechanisms and clinical relevance require further validation. This review examines the roles and molecular mechanisms of ferroptosis in podocyte injury in DKD. It also summarizes relevant pharmacological agents and other candidate interventions and discusses the therapeutic potential and future directions of targeting ferroptosis in DKD.