NLRP3 inflammasome in cardiovascular diseases: molecular mechanisms and advances in targeted drug research

Abstract

The NLRP3 inflammasome plays a pivotal role in innate immune responses and has emerged as an important contributor to the pathogenesis of cardiovascular diseases (CVDs), including atherosclerosis, heart failure, myocardial infarction, and hypertension-related organ damage. Upon activation, NLRP3 promotes the maturation and release of IL-1β and IL-18 and triggers pyroptosis, thereby exacerbating endothelial dysfunction, vascular smooth muscle cell proliferation and migration, lipid metabolic disorders, and adverse myocardial remodeling. These processes form a self-perpetuating cycle of inflammation and tissue injury. Therapeutic strategies targeting the NLRP3 pathway have progressed from non-specific anti-inflammatory agents, such as aspirin and colchicine, to more precise interventions that block NLRP3 oligomerization (e.g., MCC950 and its analogs), neutralize upstream cytokines, modulate metabolic and oxidative stress pathways, and employ advanced delivery systems including gene editing and nanocarriers. Despite these advances, current approaches are limited by insufficient target specificity, incomplete long-term safety data, and the absence of disease subtype-specific regimens. This review provides a comprehensive overview of multi-level therapeutic strategies directed against the NLRP3 inflammasome, critically evaluates preclinical and clinical evidence—including findings from the CANTOS trial—and discusses the translational potential of NLRP3-targeted immunometabolic therapy in CVDs. Looking forward, integration of multi-omics technologies, such as single-cell sequencing and spatial transcriptomics, with well-designed clinical studies will be essential to delineate the context-specific roles of NLRP3 across different CVD subtypes and to clarify its interactions with protective pathways such as AMPK and SIRT1. These efforts may facilitate the development of more selective, tissue-targeted, and safer therapeutic agents for the precision management of cardiovascular diseases.