Abstract
Ferroptosis is a regulated, iron-dependent form of cell death driven by lipid peroxidation and distinct from apoptosis, necroptosis, and pyroptosis. Recent studies implicate ferroptosis as a central contributor to the pathogenesis of renal fibrosis, a hallmark of chronic kidney disease associated with high morbidity and progression to end-stage renal failure. This review synthesizes current evidence linking ferroptotic signaling to fibrotic remodeling in the kidney, focusing on iron metabolism dysregulation, glutathione peroxidase 4 (GPX4) inactivation, lipid peroxide accumulation, and ferroptosis-regulatory pathways such as FSP1-CoQ10-NAD(P)H and GCH1-BH4. We detail how ferroptosis in tubular epithelial cells modulates pro-fibrotic cytokine release, macrophage recruitment, and TGF-β1-driven extracellular matrix deposition. Moreover, we explore ferroptosis as a therapeutic vulnerability in renal fibrosis, highlighting promising agents including iron chelators, GPX4 activators, anti-lipid peroxidants, and exosome-based gene delivery systems. By consolidating emerging preclinical data, this review provides a comprehensive mechanistic framework and identifies translational opportunities for targeting ferroptosis in fibrotic kidney disease.