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. 2022 Aug 13;13(1):29–53. doi: 10.1016/j.apsb.2022.08.007

Figure 2.

Figure 2

The canonical and non-canonical pathways of MI/R-induced pyroptosis and potential interventions. DAMPs such as ROS and HMGB1 bind to TLR4 and activate the MYD88/NF-κB/ASC/caspase-1/NLRP3 pathway in the canonical pathway. After the formation of the NLRP3 inflammasome, caspase-1 becomes active caspase-1, which cleaves pro-IL-1β to IL-1β, pro-IL-18 to IL-18, GSDMD to GSDMD-N. In the non-canonical pathway, MI/R activates caspase-4/5/11, and caspase-4/5/11 directly cleaves GSDMD to GSDMD-N. GSDMD-N then forms pores in the plasma membrane, causing pyroptosis and secretion of IL-1β, IL-18. Emodin, CREAE, CA, Bay 11-7082, miR-100-5p, M2 exosome, H2, S3680, MCC950, Gastrodin, β-asarone, and NAC reduce cardiomyocyte/myocardial damage against MI/R by targeting canonical and non-canonical pathway of pyroptosis, leading to the reduction of GSDMD. ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; CA, cinnamic acid; CREAE, ethyl acetate extract of Cinnamomi ramulus; DAMPs, damage-associated molecular patterns; GSDMD, Gasdermin D; GSDMD-N, Gasdermin D N-terminal fragment; HMGB1, high-mobility group box 1; IL, interleukin; M2 exosome, M2 macrophage-derived exosomes; MI/R, myocardial ischemia/reperfusion injury; miR, microRNA; MYD88, myeloid differentiation factor 88; NAC, N-acetyl cysteine; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; ROS, reactive oxygen species; TLR4, toll-like receptor 4.