Fig. 4: Mechanisms of pyroptosis in myocardial I/R injury.

The caspase-1-dependent pathway involves the activation of caspase-1 through the formation of inflammasomes, such as the NLRP3 inflammasome. After injury, the inflammasome formed by NLRP3, ASC, and procaspase-1 is activated. Procaspase-1 is activated as caspase-1 to cleave GSDMD, causing pore formation in the cell membrane, leading to cell swelling and lysis. The GSDMD executes the inflammasome, inducing the release of inflammatory markers associated with inflammasome activation, such as IL-1β and IL-18, ultimately leading to pyroptosis. NLRP3 is activated by ROS burst from myocardial I/R injury and Ca²⁺ overload. Extracellular LPS activates pyroptosis via the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway, aggravating myocardial I/R injury. The non-classical pathway involves direct recognition of cytoplasmic LPS by caspase-4/5/11, resulting in oligomerization and activation, leading to GSDMD cleavage and pore formation in the cell membrane. LPS lipopolysaccharide, TLR4 toll-like receptor 4, MyD88 myeloid differentiation primary response 88, GSDMD gasdermin D, NLRP3 nucleotide-binding oligomerization domain-like receptor protein 3, ASC apoptosis-associated speck-like protein containing CARD, Casp caspase, NF-κB nuclear factor-Κb, IL-1β interleukin-1 beta, IL-18 interleukin-18.