Figure 2.

Molecular mechanism of pyroptosis. In the canonical inflammasome signaling pathway, PAMPs, DAMPs, and extracellular ATP are stimulated by intracellular signaling molecules and assembled with pro-caspase-1 and ASC to form inflammasomes and activated caspase-1. N-GSDMD perforates cell membranes by forming non-selective pores. In addition, IL-1β and IL-18 were secreted in the pores formed by N-GSDMD. In the non-canonical inflammasome signaling pathway, intracytoplasmic LPS activates caspase-4/5/11, which triggers pyroptosis by cleaving GSDMD. However, oxPAPC competes with LPS for binding to caspase-4, thereby inhibiting pyroptosis. Cleavage of GSDMD leads to K+ efflux that ultimately mediates the assembly of the NLRP3 inflammasome. Moreover, cleavage of GSDMD leads to cleavage of pro-IL-1β and pro-IL-18. In the caspase-3-mediated pathway, active caspase-3 cleaves GSDME to form N-GSDME, inducing pyroptosis. In the caspase-8-mediated pathway, inhibition of TAK1 induces the activation of caspase-8, which cleaves GSDMD, leading to pyroptosis. In addition, under hypoxia, TNF-α activates caspase-8 after apoptosis to pyroptosis, which can regulate the transcription of GSDMC.