(A) Diverse microbial and cellular stress signals are detected by the sensor proteins of the canonical inflammasomes resulting in the recruitment of adaptor protein ASC and procaspase-1 resulting in inflammasome assembly which yields active caspase-1. Proinflammatory cytokines pro-IL-1β and pro-IL-18 are processed by caspase-1 to release mature IL-1β and IL-18. Caspase-1 can initiate pyroptosis by cleaving GSDMD to generate active GSDMD-NT which forms pores in the plasma membrane by targeting phospholipids resulting in pyroptosis, although other caspase-1 substrates capable of inducing pyroptosis may also exist. IL-1β and IL-18 are presumably released by cell lysis during pyroptosis. (B) The non-canonical inflammasome pathway is triggered by cytosolic Gram-negative bacteria or bacterial LPS in the infected cells resulting in activation of caspase 11 in mice (caspase-4/5 in humans) which cleaves GSDMD initiating pyroptosis. In the first step, the GSDMD pores allow potassium release, resulting in the activation of the NLRP3 inflammasome and IL-1β/IL-18 maturation. In a second step, GSDMD pores cause pyroptosis, thereby driving the release of mature cytokines. (C) Granzymes initiate GSDMB-NT- and GSDME-NT-induced pyroptosis. GzmA or GzmB, which is released from killer cytotoxic lymphocytes, induces GSDMB- or GSDME-dependent pyroptosis in tumor cells, respectively. (D) The intrinsic or extrinsic apoptotic pathway can activate caspase-3 which cleaves GSDME to produce the pyroptotic GSDME-NT, leading to membrane permeabilization and releases of proinflammatory DAMP molecules such as high mobility group box protein 1 (HMGB1), subsequently inducing secondary necrosis in macrophages. ASC, apoptosis-associated speck-like protein containing a CARD; AIM2, absent from melanoma 2; GSDMD, gasdermin D; GSDME, gasdermin E; GSDMB, gasdermin B; GzmA, granzyme A; GzmB, granzyme B; HMGB1, high mobility group box protein 1; IL-1β, interleukin-1β; IL-18, interleukin-18, LPS, lipopolysaccharide; NLRP3, Nod-like receptor (NLR) pyrin domain-containing 3; NLRC4, NLR family CARD domain-containing protein 4.