Figure 3.

Mechanisms of NLRP3 inflammasome and pyroptosis in DCM. Taking cardiomyocytes as an example, hyperglycemia increases the generation of intracellular ROS, induced by mitochondrial dysfunction, which causes the separation of TXNIP from TRX and binds to NLRP3. This process results in NLRP3 inflammasome activation and pro-caspase-1 autocleavage. Additionally, ROS activates NF-κB, promoting the construction of molecular platform for NLRP3 inflammasome and self-cleavage of caspase-1, then facilitates the procession of IL-1β and IL-18. Activated caspase-1 also promotes GSDMD cleavage into its active form, subsequently inducing membrane pore formation and leading to cellular swelling and pyroptosis. CY-09 and MCC950 are the special inhibitors of NLRP3, which can exert an inhibitory effect by combining directly into ATP-binding motif of NACHT domain and restraining the ATPase activity of NLRP3. DMF can respond to GSDMD at a pivotal cysteine residue to promote GSDMD succination, then affects the interaction between GSDMD and caspases and consequent reactions. Disulfiram, a potent inhibitor of GSDMD, can abolish the formation of plasma membranes pore induced by GSDMD.