Iron-Dependent Regulated Cell Death in Acute Kidney Injury: From Molecular Pathways to Clinical Translation

Acute kidney injury (AKI) remains a critical syndrome with high morbidity and mortality in hospitalized patients, yet current diagnostic approaches relying on serum creatinine and urine output lack sensitivity for early detection. Ferroptosis, an iron-dependent regulated cell death distinct from apoptosis and necrosis, has emerged as a central mechanism in AKI pathogenesis, particularly in ischemia-reperfusion injury, sepsis-associated AKI, contrast-induced nephrotoxicity, and drug-induced kidney injury. This review synthesizes evidence establishing ferroptosis as a convergent pathophysiological mechanism across diverse AKI etiologies through dysregulation of three critical systems: iron metabolism (transferrin receptor-mediated uptake, NCOA4-mediated ferritinophagy), lipid peroxidation (ACSL4-driven PUFA incorporation, lipoxygenase-catalyzed oxidation), and antioxidant collapse (System Xc⁻ dysfunction, glutathione depletion, GPX4 inactivation). Ferroptosis initiates a pathogenic cascade linking acute tubular cell death to chronic kidney disease through ferroptosis-driven senescence, NLRP3 inflammasome activation, and TGF-β/Smad-mediated fibrosis, explaining the AKI-to-CKD progression observed clinically. Emerging evidence supports ferroptosis-specific biomarkers including urinary lipid peroxidation products, tubular injury markers (KIM-1, NGAL), and systemic iron metabolism indicators (hepcidin, ferroportin), enabling non-invasive monitoring via exosomal liquid biopsy. Therapeutic strategies targeting ferroptosis through iron chelation, lipid peroxidation inhibitors (ferrostatin-1, liproxstatin-1), antioxidant system restoration, Nrf2 activation, and mitochondrial-targeted therapies show preclinical promise. Integration of ferroptosis biology into clinical practice through targeted diagnostics and precision therapeutic approaches offers substantial potential for transforming AKI management, preventing chronic sequelae, and improving long-term renal outcomes.