Fig. 3

Schematic representation of pyroptosis signaling pathways. A In the canonical pathway, PRRs detect DAMPs or PAMPs that stimulate inflammasomes, which then activate caspase-1 to cleave GSDMD to form N-GSDMD and C-GSDMD. Meanwhile, caspase-1 activates pro-IL-1β and pro-IL-18 to form mature IL-1β and IL-18, respectively. The the N-GSDMD domains then bind to the plasma membrane to form pores, which allows IL-1β and IL-18 secretion, eventually resulting in cell swelling and membrane rupture. B In the noncanonical pathway, caspase-4/5/11 can directly bind to cytosolic LPS and be activated. Then caspase-4/5/11 cleave GSDMD to promote pyroptosis. C In other alternative pathways, chemotherapy drugs or TNF switch apoptosis to pyroptosis through the caspase-3-GSDME axis. GZMB from NK and CD8⁺ T cells can also cleave GSDME directly or by activating caspase-3 to form N-GSDME to induce pyroptosis. GZMA secreted from NK and CD8⁺ T cells promotes GSDMB-mediated pyroptosis. Under hypoxic conditions, GSDMC are cleaved by activated caspase-8. The caspase-8 also cleaves GSDMD in the intestinal epithelial cells to induce pyroptosis. In neutrophils, neutrophil elastase and cathepsin G cleave GSDMD to induce pyroptosis. Streptococcal pyrogenic exotoxin B induces pyroptosis via GSDMA cleavage. PRRs Pattern recognition receptors, DAMPs Damage-associated molecular patterns, PAMPs Pathogen-associated molecular patterns, GSDMD Gasdermin D, GZMB Granzyme B, GZMA Granzyme A, NK Natural killer