Ferroptosis is a recently characterized form of regulated cell death distinct from apoptosis and necroptosis. Which of the following BEST characterizes the mechanism and morphology of ferroptosis?

• A Ferroptosis is triggered by caspase-8 activation following TRAIL receptor engagement, producing chromatin margination and membrane blebbing identical to apoptosis
• B Ferroptosis is mediated by MLKL pore formation in the plasma membrane, causing osmotic lysis identical to necroptosis
• C Ferroptosis results from iron-dependent accumulation of lipid peroxides due to inactivation of glutathione peroxidase 4 (GPX4), producing cell death with mitochondrial morphological changes (shrunken mitochondria with increased membrane density) without caspase activation or nuclear fragmentation ✓
• D Ferroptosis requires BNIP3L-mediated selective autophagy of ferritin, releasing toxic free iron that damages the nucleus causing chromatin condensation

Explanation

Ferroptosis is a form of regulated, non-apoptotic cell death driven by iron-dependent accumulation of lipid hydroperoxides. The key regulatory node is GPX4 (glutathione peroxidase 4), which normally reduces phospholipid hydroperoxides using glutathione; when GPX4 is inactivated (by ferroptosis inducers like RSL3 or by glutathione depletion via cystine/glutamate antiporter inhibition with erastin), lipid peroxides accumulate and damage the plasma membrane. Morphologically, ferroptosis shows shrunken mitochondria with increased membrane density, but no chromatin condensation, caspase activation, or nuclear fragmentation — distinguishing it from apoptosis. Necroptosis uses MLKL pore formation, which is distinct.

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

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