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).
Organ Systems
immune-hematologic
integumentary
Pathway Steps
DAMP / PAMP (cholesterol crystals, β-amyloid, ATP, MSU, LPS) → NLRP3 / NLRC4 / AIM2 / pyrin inflammasome assembly — via sensor-specific activation; NLRP3 = 2-signal model (priming + activation). Pyroptosis starts when cytosolic sensors detect danger: NLRP3 (broad DAMPs — cholesterol crystals, β-amyloid, ATP, urate), NLRC4 (bacterial flagellin/T3SS), AIM2 (cytosolic dsDNA), or pyrin assemble into inflammasomes. NLRP3’s two-signal requirement makes it the central hub of sterile inflammation and a major drug target.
inflammasome → ASC oligomerization → caspase-1 activation — via ASC speck = signaling hub; release also primes adjacent cells. Inflammasome assembly nucleates the adaptor ASC into a single micron-scale speck, which clusters pro-caspase-1 to drive its proximity-induced autoactivation. The ASC speck is both an amplifier and a visible hallmark of an active inflammasome, and it can be released to propagate inflammation between cells.
caspase-1 → GSDMD cleavage at Asp275 → N-terminal fragment — via parallel: cleaves pro-IL-1β + pro-IL-18 → mature cytokines. Active caspase-1 has two jobs: it matures the cytokines IL-1β/IL-18, and it cleaves gasdermin D at Asp275, freeing its pore-forming N-terminal domain from the autoinhibitory C-terminus. This cleavage is the committing step that turns an inflammasome signal into membrane-lytic death.
GSDMD-N (cytosolic) → plasma membrane oligomerization → 10–16-mer pores — via 15 nm inner diameter; lytic; IL-1β/IL-18 release. Freed GSDMD-N targets the inner leaflet’s acidic lipids, oligomerizes, and punches large (10–16-subunit) plasma-membrane pores. These release IL-1β/IL-18 and cause osmotic lysis — the lytic, pro-inflammatory death that distinguishes pyroptosis from apoptosis; NINJ1 then drives the final membrane rupture.
cytosolic LPS (gram-negative) → caspase-4/5/11 → GSDMD cleavage — via non-canonical pathway; sepsis mechanism. A non-canonical route bypasses the inflammasome: cytosolic LPS from gram-negative bacteria binds caspase-4/5 (human) or caspase-11 (mouse) directly, which then cleave GSDMD themselves. This lets cells sense intracellular gram-negative infection and is central to LPS-driven sepsis.
caspase-3 (apoptosis) + GSDME expression → switch to pyroptosis — via chemotherapy-induced pyroptosis when GSDME is expressed (CDDP). The death programs cross-talk: when apoptotic caspase-3 is active in a cell expressing gasdermin E (GSDME/DFNA5), caspase-3 cleaves GSDME to open pores — converting “silent” apoptosis into lytic pyroptosis. GSDME is silenced in many tumors, so its re-expression shapes chemotherapy-induced inflammation.