FIGURE 2.

The main molecular mechanism of pyroptosis. In the caspase-1-dependent canonical inflammasome pathway, various inflammasomes are stimulated by cellular signals (such as PAMPs and DAMPs), which activate the inflammasomes and caspase-1. The activated caspase-1 cleaves GSDMD and pro-IL-1β/pro-IL-18, and finally mature IL-1β and IL-18 flow out of the GSDMD pore formed by the N-GSDMD oligomerization. In the caspase-4/5/11-dependent noncanonical inflammasome pathway, cytosolic LPS directly activates caspase-4/5/11, and the corresponding activated caspases will cleave GSDMD and eventually trigger pyroptosis. In the caspase-3-mediated pathway, chemotherapy drugs can directly activate caspase-3/GSDME-mediated pyroptosis. And molecular targeted therapies will elicit mitochondrial dysfunction and activate caspase-9, which eventually promote caspase-3/GSDME-mediated pyroptosis. In addition, the stimulation of high bile acid levels can result in MPT, then promoting Apaf-1/caspase-4/11 pyroptosome assembly, and ultimately causing caspase-3/GSDME-dependent pyroptosis. Caspase-3 can also be activated via caspase-8 when death ligands/receptors are stimulated. In the caspase-8-mediated pathway, in the response to LPS (such as Yersinia), the inhibition of TAK1/IKK complex activates caspase-8, and then triggers GSDMD-mediated pyroptosis. Moreover, under hypoxic conditions, PD-L1 binds to p-Stat3 in the nucleus, converting TNF-α-induced apoptosis into caspase-8/GSDMC-mediated pyroptosis. Besides, the metabolite α-KG can increase ROS production, promoting the assembly of DR6/pro-caspase-8/GSDMC receptosome, and activated caspase-8 cleaves GSDMC, leading to pyroptosis. In granzyme-mediated pathway, the CAR T cells rapidly activate caspase-3 by releasing GzmB, then GSDME-mediated pyroptosis is induced, and GzmB can directly act on GSDME. The GzmA derived by NK cells and lymphocytes could cleave GSDMB to result in pyroptosis.