Fig. 2.

Critical molecular pathways involved in pyroptosis. This figure displays the four principal pyroptotic signaling pathways: (A) canonical, (B) non-canonical, (C) granzyme-dependent, and (D) caspase-3/8-dependent. A Canonical pathway; PAMP and DAMP perception triggers activation of the NLRP3 inflammasome, which sequesters adaptor protein ASC and pro-caspase-1. Activated caspase-1 cleaves GSDMD, generating N-GSDMD fragments that form membrane pores, allowing for secretion of IL-1β and IL-18 and leading to pyroptotic lysis. B The non-canonical pathway is direct intracellular LPS activation of caspase-4/5 (humans) or caspase-11 (mice), proteolytic cleavage of GSDMD and leading to pore formation, which also has the ability to activate NLRP3 inflammasome. C In the granzyme-dependent pathway, cytotoxic lymphocytes release granzymes A and B. Granzyme B proteolytically cleaves GSDME, and Granzyme A cleaves GSDMB, to produce pore-forming N-GSDME and N-GSDMB fragments, respectively, to execute pyroptosis. D Caspase-3/8-dependent pathway bridges the pyroptotic and apoptotic pathways. Cleavage of GSDME, GSDMD, or GSDMC by stressors such as infection (Yersinia), hypoxia, or chemotherapy agents activates caspase-3 or −8 and triggers inflammatory cell death. In this pathway, transcription factors such as STAT3 and immune checkpoint proteins such as PD-L1 might regulate the expression of GSDMC and thus the pathway choice between apoptosis and pyroptosis. Collectively, these interconnected pathways depict the molecular heterogeneity of pyroptosis and its role in immunity-mediated inflammation and cell death