Ferroptosis is a recently characterized regulated cell death modality. Which of the following best describes the central biochemical mechanism of ferroptosis?
- A Caspase-3 and -7 activation cleaving GSDMD to form plasma membrane pores
- B RIPK3-MLKL pathway forming pores in the plasma membrane causing oncotic swelling
- C NLRP3 inflammasome-mediated caspase-1 activation cleaving pro-IL-1β and pro-GSDMD
- D Iron-dependent peroxidation of polyunsaturated fatty acid (PUFA) phospholipids in the plasma membrane due to GPX4 inactivation ✓
Explanation
Ferroptosis is an iron-dependent, caspase-independent regulated cell death driven by accumulation of lethal lipid peroxides, specifically peroxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) in the plasma membrane. The central regulatory checkpoint is GPX4 (glutathione peroxidase 4), which reduces phospholipid hydroperoxides to phospholipid alcohols using glutathione as cofactor. When GPX4 is inactivated (e.g., by RSL3) or when glutathione is depleted (e.g., by system Xc- inhibitor erastin blocking cystine import), PUFA-PLs undergo iron-catalyzed peroxidation causing membrane destruction. Caspase-3/GSDMD describes pyroptosis; RIPK3-MLKL is necroptosis; NLRP3-caspase-1-GSDMD is also pyroptosis.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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