Ferroptosis, a non-apoptotic regulated cell death mechanism relevant to degenerative diseases and cancer cell death, is fundamentally driven by:
- A Lysosomal membrane permeabilization with cathepsin release causing cytoplasmic protein hydrolysis
- B ER stress-mediated activation of the PERK-eIF2alpha branch of the unfolded protein response leading to CHOP-dependent apoptosis
- C Iron-catalyzed lipid peroxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids, inhibited by GPX4 (glutathione peroxidase 4) converting lipid hydroperoxides to lipid alcohols ✓
- D Parthanatos — PARP1 hyperactivation and NAD+ depletion causing AIF nuclear translocation and chromatinolysis
Explanation
Ferroptosis is defined by iron-dependent accumulation of lipid peroxides, specifically from oxidation of PUFA phospholipids in cellular membranes. The rate-limiting suppressor of ferroptosis is GPX4, a selenoprotein glutathione peroxidase that uses glutathione (GSH) to reduce lipid hydroperoxides to non-toxic lipid alcohols. Depletion of cysteine (the rate-limiting GSH precursor) via system Xc− inhibition, or direct GPX4 inhibition, triggers ferroptotic lipid peroxide accumulation and membrane disruption. Iron participates via Fenton-like reactions generating reactive lipid species. Lysosomal death, ER stress, and parthanatos are distinct regulated cell death modalities not primarily dependent on lipid peroxidation.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.