Figure 2.

The noncanonical pyroptosis pathway. Endotoxin can activate caspase-11 in mice or caspase-4, 5 in humans to mediate the noncanonical pyroptosis pathway. After activated, caspase-4, 5, 11 cleave GSDMD to generate GSDMD-N, resulting in plasma membrane perforation. At the same time, GSDMD-N activates NLRP3, which activates caspase-1 and initiates the canonical pyroptosis pathway. In addition, by specifically binding to LPS, caspase-11 can facilitate the expression of Pannexin-1. Activated Pannexin-1 activates the P2X7 channel, releasing ATP and K⁺, further damaging the integrity of the cell membrane. Endotoxin can also activate the NF-κB pathway and promote the expression and release of IFN-β.