Fig. 2.

GSDMD-mediated pyroptosis and rupture of the plasma membrane. DAMPs and PAMPs stimulate inflammasome assemblies formation and caspase-1 activation in the canonical pyroptosis pathway, as well as caspase-11 activation (human caspase-4/5) in the non-canonical pyroptosis pathway. Upon activation, caspase-1/11/4/5 cleaves GSDMD to produce GSDMD-NT. Simultaneously, caspase-1 matures pro-IL-1β and pro-IL-18. Moreover, caspase-4 non-canonical inflammasome also matures IL-18. GSDMD-NT assembles into oligomeric pores on the plasma membrane, mediating the release of small molecules such as IL-1β/IL-18, and K⁺ efflux facilitates NLRP3 inflammasome assembly. Water permeates pyroptotic cells, leading to swelling and NINJ1-dependent PMR. Concurrently, the discharge of large intracellular molecules, including LDH and DAMPs such as HMGB1, is observed. Moreover, the activation of caspase-11 results in the cleavage of Pannexin-1, which in turn facilitates ATP release and orchestrates P2X7-associated cell death. Two mechanisms can repair membrane damage induced by the GSDMD pore: endosomal sorting complexes required for transport (ESCRT); and ceramide for endocytic repair of the GSDMD pores