Ferroptosis regulation by SGLT2 inhibitors: mechanisms and clinical benefits in diabetic kidney disease

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease and remains inadequately managed by conventional therapies focused on glucose control and hemodynamics. Growing evidence suggests that ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a critical role in renal tubular injury, oxidative stress, and fibrosis in DKD. The diabetic renal microenvironment is characterized by dysregulated iron handling, impaired antioxidant capacity, and lipid metabolic reprogramming, all of which converge to promote ferroptotic vulnerability. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have emerged as cornerstone agents in DKD treatment, conferring substantial renoprotective benefits beyond glycemic control. Recent studies indicate that SGLT2 inhibitors regulate ferroptosis through different mechanisms. The effects include correcting iron imbalances associated with hypoxia, enhancing fatty acid β-oxidation, and strengthening the antioxidant defense system by activating the AMP-activated protein kinase (AMPK)-nuclear factor erythroid 2–related factor 2 ( NRF2 )-glutathione peroxidase 4 ( GPX4 ) axis. Furthermore, ferroptosis-related biomarkers in serum and urine display disease stage–dependent alterations, highlighting their potential utility for patient stratification and therapeutic response prediction. This review elucidates how SGLT2 inhibitors promote renal protection in DKD by regulating ferroptosis, supported by both mechanistic insights and clinical evidence. It also addresses unresolved issues in its current clinical application. Furthermore, this work proposes a promising pharmacological strategy for the prevention and treatment of DKD.