A patient with ischemia-reperfusion injury to the kidney shows massive tubular cell death on reperfusion despite having had only modest injury during ischemia itself. Which iron-dependent mechanism of cell death, distinct from apoptosis and classical necrosis, is now recognised as a key driver of this injury?

• A Ferroptosis — iron-catalysed peroxidation of polyunsaturated fatty acid phospholipids via GPX4 inactivation ✓
• B Parthanatos — PARP-1 hyperactivation consuming NAD+/ATP leading to AIF-dependent nuclear death
• C Cuproptosis — copper-mediated disruption of lipoylated TCA cycle proteins
• D Oxeiptosis — KEAP1/PGAM5/AIFM2-mediated apoptosis-independent oxidative cell death

Explanation

Ferroptosis is a regulated, non-apoptotic, iron-dependent cell death characterised by unrestricted peroxidation of polyunsaturated fatty acid (PUFA) phospholipids in cell membranes. During reperfusion, reactive oxygen species react with free iron (released from mitochondria and ferritin) to generate lipid peroxides via the Fenton reaction. GPX4 (glutathione peroxidase 4) normally reduces these lethal lipid peroxides; when GPX4 is inactivated or GSH is depleted, lipid peroxides accumulate and cause membrane disruption. Ferroptosis is a major mechanism of AKI in ischemia-reperfusion injury and can be attenuated by ferrostatin-1. Parthanatos involves PARP hyperactivation and AIF release but is not lipid-peroxidation-dependent.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.