Fig. 2

Signaling pathways of pyroptosis. In the canonical pathway of pyroptosis, PAMPs, and DAMPs are stimulated by intracellular signaling molecules. They combine with pro-caspase-1 and the adaptor protein ASC to form inflammasomes, leading to the activation of caspase-1. Cleaved caspase-1 then proceeds to cleave GSDMD and pro-IL-1β/IL-18. N-terminal GSDMD forms non-selective pores in the cell membrane, resulting in water influx, cell lysis, and ultimately cell death. Additionally, IL-1β and IL-18 are released through the pores formed by N-terminal GSDMD. In the non-canonical pathway, LPS activates caspase-4/5/11, triggering pyroptosis by cleaving GSDMD. The cleavage of GSDMD also leads to the efflux of K⁺, facilitating the assembly of the NLRP3 inflammasome and cleavage of pro-IL-1β and pro-IL-18. In the caspase-8-mediated pathway, the inhibition of TAK1 leads to the activation of caspase-8, which cleaves GSDMD, resulting in pyroptosis. Under hypoxic conditions, PD-L1 translocates to the nucleus and, in conjunction with phosphorylated Stat3, regulates the transcription of GSDMC, leading to the conversion of apoptosis to pyroptosis following TNFα-activated caspase-8. In the granzyme-mediated pathway, CAR-T cells rapidly activate caspase-3 in target cells by releasing GzmB. Subsequently, GSDME is activated, causing extensive pyroptosis. GzmA and GzmB from cytotoxic lymphocytes enter target cells through perforin and induce pyroptosis. GzmA hydrolyzes GSDMB, and GzmB directly activates GSDME. The figure was created by Figdraw