Iron-Driven Ferroptosis in Diabetic Kidney Disease: From Molecular Mechanisms to Targeted Therapeutic Translation

Abstract

Abstract Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease worldwide, and current standard treatments cannot fully halt its progressive decline in renal function. Dysregulated iron metabolism and its downstream induction of ferroptosis — an iron-dependent, lipid peroxidation-driven form of regulated cell death — have now been recognized as a key pathogenic driver of renal injury in DKD. This narrative review systematically synthesizes up-to-date evidence on how aberrant iron uptake, storage and export in renal cells trigger ferroptosis, disrupt antioxidant defenses, and promote renal tubular damage, glomerular sclerosis and interstitial fibrosis. We clearly distinguish mechanistic findings from preclinical in vitro and in vivo studies from clinically validated observations, including emerging ferroptosis-related biomarkers detected in DKD patient cohorts. We further evaluate iron chelation, lipid peroxidation inhibition, and targeted antioxidant reinforcement as promising therapeutic strategies, while explicitly highlighting critical current limitations: the lack of fully validated, kidney-specific ferroptosis biomarkers, insufficient large-scale clinical trial evidence, poor targeted delivery to renal parenchyma, and unresolved safety risks of long-term iron modulation. In conclusion, targeting iron-driven ferroptosis represents a highly promising translational direction for DKD intervention, but rigorous validation of ferroptosis-related biomarkers, optimization of kidney-targeted delivery systems, and well-designed clinical trials are still required before these strategies can be reliably translated into routine clinical practice.