Targeting NLRP3 Inflammasome Signaling After Myocardial Infarction: Mechanistic Rationale, Regulatory Networks, and Translational Perspectives

Myocardial infarction (MI) remains a major cause of death and heart failure despite advances in reperfusion and secondary prevention. Sterile inflammation triggered by ischemic myocardial injury is increasingly recognized as a determinant of infarct expansion, adverse ventricular remodeling, and subsequent clinical outcomes. The NOD-like receptor protein 3 (NLRP3) inflammasome integrates danger-associated molecular patterns, mitochondrial dysfunction, ionic disturbance, metabolic stress, and innate immune signaling. Following activation, caspase-1 processes interleukin-1β and interleukin-18 and cleaves gasdermin D to generate the pore-forming GSDMD-N fragment, thereby promoting pyroptosis and inflammatory amplification. After MI, NLRP3 activity is shaped by extracellular adenosine triphosphate and P2X7 signaling, potassium efflux, reactive oxygen species, mitochondrial DNA release, lysosomal and endoplasmic reticulum stress, and cyclic GMP-AMP synthase-stimulator of interferon genes signaling. Importantly, these responses are temporally and cell-type dependent: cardiomyocytes, macrophages, endothelial cells, and fibroblasts contribute differently to injury, debris clearance, vascular dysfunction, scar formation, and repair. This review differs from earlier pathway-centered summaries by integrating temporal regulation and cell-specific biology with emerging crosstalk among mitochondrial quality control, STING signaling, ferroptosis, pyroptosis, and immunometabolism. Translational evidence is considered alongside mechanism, including interleukin-1-directed studies such as CANTOS and the Virginia Commonwealth University Anakinra Remodeling Trial program, while emphasizing that clinical benefit from selective NLRP3 inhibition itself remains to be established. Direct inflammasome inhibitors, colchicine, metabolic modulators, RNA-based approaches, targeted delivery systems, and traditional Chinese medicine-derived compounds are critically discussed with attention to evidence level and limitations. We further examine biomarker-guided patient selection and unresolved questions concerning therapeutic timing, cell specificity, long-term safety, and preservation of reparative inflammation.