Figure 1.

Molecular mechanism of pyroptosis. In the caspase-1-dependent pathway, PAMPs and DAMPs mediate inflammasome assembly and activate caspase-1, which cleaves GSDMD and pro-IL-1β/18. N-GSDMD forms non-selective pores on the cell membrane surface, and IL-1β and IL-18 are secreted out of the cell membrane through the pores formed by N-GSDMD, which further leads to cell lysis and death. In the caspase-1-independent pathway, LPS of bacteria activates caspase-4/5/11 and cleaves GSDMD to trigger pyroptosis. However, caspase-4/5/11 can also activate inflammasome assembly and caspase-1 to induce pyroptosis. In addition, in the caspase-8-mediated pathway, TNF-α induces the activation of caspase-8, cleavage of GSDMD leads to pyroptosis, and caspase-8 can also cleave GSDMC and GSDME, Furthermore, the NLRP3 inflammasome also activate Caspase-8. Granzyme also mediates pyroptosis, such as GzmB released from CAR T cells induces pyroptosis by activating caspase-3 and cleaving GSDME. In the caspase-9-mediated pathway, chemotherapy drugs and iron cause mitochondrial stress, activate caspase-3/9, and cleave GSDMB/E to mediate pyroptosis. Furthermore, GzmA in cytotoxic leukomonocyte enters target cells via perforin and cleaves GSDMB resulting in cell pyroptotic death. Similarly, GSDMB/C/E also forms pores to mediate the secretion of inflammatory mediators out of the membrane, amplify the inflammatory response, and promote cell death.