Pyroptosis in myocardial ischemia-reperfusion injury: mechanistic pathways and therapeutic prospects

Acute myocardial infarction (AMI) remains the leading cause of cardiovascular death and disability worldwide. With the advances in percutaneous coronary intervention and coronary artery bypass grafting, timely revascularization has become the main approach to limit infarct size and improve heart function and prognosis. However, the sudden restoration of blood flow during reperfusion can actually accelerate heart muscle cell death by worsening inflammation, calcium overload, and oxidative stress, a phenomenon known as myocardial ischemia-reperfusion injury (MIRI). Pyroptosis, a lytic and highly pro-inflammatory form of programmed cell death executed by members of the gasdermin family, has emerged as a central mechanism linking cell death to inflammation in MIRI. This review summarizes the molecular pathways of pyroptosis, including the canonical NLRP3/caspase-1/GSDMD axis, non-canonical caspase-4/5/11 activation, and the caspase-3/GSDME pathway, and profiles the roles of individual gasdermin family members in MIRI. We then delineate how pyroptosis operates in cardiomyocytes, cardiac fibroblasts, vascular endothelial cells, and macrophages; how it is modulated by oxidative stress, calcium overload, and autophagy. We further evaluate therapeutic agents acting at distinct nodes of this cascade, including NLRP3 inhibitors, caspase inhibitors, GSDMD inhibitors, repurposed drugs, and natural products, and assess the experimental models and levels of evidence supporting them. We conclude that pyroptosis is a promising therapeutic target for MIRI. Nevertheless, the available evidence is still dominated by preclinical studies of GSDMD, and several issues remain unresolved, including cell type-specific regulatory mechanisms, the roles of gasdermin family members beyond GSDMD, and key translational challenges.