Ferroptosis and Tubular Injury: Molecular Drivers of Renal Damage, Maladaptive Repair, and Disease Progression

Abstract

Ferroptosis has been shown to be a significant regulated cell death mechanism that associates renal tubular injury with maladaptive repair and progressive renal dysfunction. This review will discuss the molecular mechanism of ferroptosis in tubular epithelial cells and the role of ferroptosis in both acute and chronic renal damage. Collectively, iron dysregulation, lipid peroxidation, depletion of glutathione, impairment of GPX4, ferroptinophagy, and disruption of NRF2 signaling all contribute to the susceptibility of the tubules to ferroptotic injury. On-going ferroptotic stress can disrupt epithelial regeneration, induce cell cycle arrest, further enhance inflammatory and profibrotic signals, and lead to tubulointerstitial fibrosis. These mechanisms link acute kidney injury, inadequate tubular recovery, the transition from acute to chronic kidney disease, diabetic kidney disease, and the loss of nephrons. Therapeutics based on iron homeostasis, lipid peroxidation, GSH–GPX4 axis, and other alternative antioxidant pathways hold promise for the prevention of renal damage associated with ferroptosis. There is a need for validated ferroptosis-specific biomarkers, better patient stratification, clinically representative models, and well-defined therapeutic windows to translate insights into mechanisms into effective renal intervention in the future.