Category: cell_death
Pyroptosis is a gasdermin-mediated lytic programmed cell death — distinct from apoptosis (no caspases 3/7 / no membrane integrity loss until late), ferroptosis (no iron requirement), and necroptosis (no RIPK3/MLKL). Two main pathways: (1) Canonical — pattern-recognition receptors (NLRP3, NLRC4, AIM2, pyrin) form inflammasomes → recruit ASC → activate caspase-1 → cleaves pro-IL-1β + pro-IL-18 to mature cytokines + cleaves GSDMD (gasdermin D) at Asp275 → liberates GSDMD-N-terminal pore-forming domain → oligomerizes into 10–16-mer pores in plasma membrane (15 nm inner diameter) → lytic death + IL-1β/IL-18 release. (2) Non-canonical — cytosolic LPS directly activates caspase-4/5/11 → same GSDMD cleavage. Also GSDME (DFNA5) — caspase-3 cleaves GSDME → switches apoptosis to pyroptosis when GSDME is expressed; relevant for chemotherapy-induced pyroptosis. Therapeutic relevance: cryopyrin-associated periodic syndromes (CAPS — NLRP3 GoF mutations); familial Mediterranean fever (FMF — pyrin); gout, pseudogout (NLRP3 → IL-1β); Alzheimer disease (β-amyloid → NLRP3 → neuroinflammation); atherosclerosis (cholesterol crystals → NLRP3 — basis for CANTOS canakinumab CV benefit); colchicine in pericarditis (NLRP3 inhibition); aspirin-induced gastric injury partly via gasdermin. Therapeutics: IL-1β neutralization (canakinumab — CV + autoinflammatory; anakinra — IL-1Ra; rilonacept — IL-1 trap); MCC950 (NLRP3 inhibitor, preclinical); colchicine (microtubule disruption + NLRP3 inhibition — LoDoCo2/COLCOT post-MI CV trials); VX-765 (caspase-1 inhibitor, abandoned epilepsy). Cross-links: [[nlrp3_inflammasome]] (upstream activator), [[tlr_innate_signaling]] (parallel innate output), [[ferroptosis_gpx4_lipid_peroxidation]] (parallel regulated cell death), [[apoptosis_bcl2_axis]] (GSDME crosstalk).