Fig. 1: Mechanisms of canonical/non-canonical pyroptosis pathway.

Extracellular and intracellular signals like bacteria and virus protein, LPS, and MSU are detected by PRRs and activate NF-kB signaling to upregulate transcription of NLRP3, pro-caspase-1, and pro-IL-1β/-18. Then NLRP3 inflammasome is assembled and activated. Caspase-1 cleaves GSDMD, and the N-terminal generates membrane pores which induce cytotoxicity. Pro-caspase-1β/-18 is also cleaved by caspase-1, and mature cytokines are released through membrane pores. The non-canonical pathway is triggered by intracellular LPS, which activates caspase-4/-5/-11 with the help of GBPs. Activated caspase-4/-5/-11 cleaves GSDMD and pro-pannexin-1 and contributes to membrane pore formation. Pannexin-1 pore has a mutual promoting effect with P2X7 pore, and they lead to K⁺ and ATP efflux and Ca²⁺ influx jointly.