Inflammasomes in Atherosclerosis and Atherothrombosis

Atherosclerotic cardiovascular disease and its thrombotic complications, particularly myocardial infarction and ischemic stroke, remain leading causes of morbidity and mortality worldwide. Atherosclerosis was historically considered primarily a lipid accumulation disorder; however, it is now well recognized as a chronic inflammatory disesse driven in large part by innate immune signaling. Inflammasomes, particularly NOD-like receptor protein 3 (NLRP3) and absent in melanoma 2 (AIM2), play important role in this process, linking vascular inflammation, plaque progression, and thrombosis through caspase-1 activation, interleukin-1 beta (IL-1β) and IL-18 release, and gasdermin-mediated pyroptosis. In this narrative review we integrate mechanistic and translational evidence defining inflammasome activity across the continuum of atherosclerosis and atherothrombosis. We highlight inflammasome signaling in endothelial cells, macrophages, vascular smooth muscle cells, platelets, neutrophils, and perivascular adipose tissue, and discuss how these pathways contribute to early inflammation, necrotic core expansion, fibrous cap destabilization, and ultimately to acute thrombus formation. Emerging data on AIM2 activation, clonal hematopoiesis, platelet inflammasomes, and cell-free deoxyribonucleic acid (DNA) further expand current paradigms beyond macrophage focused models on macrophages. We also review single-cell and spatial transcriptomics, circulating biomarkers, and advanced vascular imaging approaches that may enable the identification of inflammasome-high atherothrombotic phenotypes. Finally, we appraise therapeutic strategies targeting inflammasomes and downstream pathways. These include IL-1β and IL-6 inhibition, colchicine, direct NLRP3 inhibition, and cardiometabolic therapies with indirect effects on inflammasome activity. By examining the role of inflammasomes in linking plaque pathogenesis to thrombosis, this review outlines key translational opportunities and challenges for the precision prevention of atherothrombosis.