Ferroptosis has been recognized as a distinct form of regulated cell death distinct from apoptosis, necroptosis, and necrosis. Which set of biochemical features correctly distinguishes ferroptosis from classical intrinsic apoptosis?

• A Ferroptosis: caspase-3 activation, nuclear fragmentation, apoptotic bodies; apoptosis: lipid peroxidation, iron dependence, necrotic morphology
• B Ferroptosis and apoptosis are mechanistically identical; the difference is only in initiating stimulus (oxidative stress vs. death receptor ligation)
• C Ferroptosis: iron-dependent accumulation of lipid peroxides in phospholipid bilayers, GPX4 inactivation, no caspase activation, morphology of organelle swelling without nuclear condensation; apoptosis: caspase cascade, cytochrome c release, nuclear condensation and fragmentation, apoptotic bodies with intact membranes ✓
• D Ferroptosis: RIPK3 and MLKL-mediated plasma membrane rupture; apoptosis: caspase-7 activation without membrane rupture

Explanation

Ferroptosis is a distinct regulated cell death pathway characterized by iron-catalyzed accumulation of lipid peroxides, specifically oxidized phosphatidylethanolamines in cellular membranes, driven by LOX enzymes and the Fenton reaction. Glutathione peroxidase 4 (GPX4) is the critical guardian that reduces lipid hydroperoxides; its inactivation (by GSH depletion or direct inhibition, e.g., by RSL3) allows lipid peroxide buildup and membrane damage. Morphologically, ferroptosis shows organelle swelling (especially mitochondrial cristae condensation) without nuclear condensation or fragmentation; there is no caspase activation and it is not blocked by pan-caspase inhibitors. Classical apoptosis involves caspase cascades, cytochrome c, nuclear condensation, and apoptotic body formation.

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

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