Molecular mechanisms of pyroptosis. The canonical pyroptosis pathway depends on the inflammasome and GSDMD by caspase-1. Activated inflammasome promotes the activation of caspase-1, which cleaves the pore-forming factor GSDMD. Active caspase-1 also cleaves the proinflammatory cytokines such as IL-1\beta and IL-18. NLRP1 initiates inflammasome activation upon anthrax toxin. NLRP3 needs to be primed prior to activation. The activators of NLRC4 are flagellin and components of T3SS, the adaptor protein ASC is not necessary for the assembly of NLRC4 inflammasome. The activators of NLRP6 are microbial metabolites and lipoteichoic acid. Rotavirus infection lead to the activation of NLRP9b. AIM2 recognizes dsDNA in the cytosol. The non-canonical pyroptosis pathway requires directly binding of LPS to caspase-11 (murine) or caspase-4/-5 (human) and release of GSDMD N-terminus. Caspase-8 mediates the cleavage of GSDMC and GSDMD. Chemotherapy drugs and TNF-\alpha promotes the activation of caspase-3, which cleaves the GSDME. Gzm B in NK cells and cytotoxic T lymphocytes can also directly cleave GSDME. Gzm A from cytotoxic lymphocytes could cleaves GSDMB. Human pathogen group A Streptococcus secretes SpeB, which induces GSDMA-dependent pyroptosis. DAMP, damage-associated molecular pattern; PAMP, pathogenassociated molecular patterns; ASC, apoptosis associated speck-like protein containing a caspase recruitment domain; LPS, lipopolysaccharide; GSDM, Gasdermin.