Atherosclerosis, the primary pathological foundation of cardiovascular mortality worldwide, is deeply intertwined with chronic inflammatory processes. In recent years, neutrophils have been recognized as pivotal contributors to all stages of atherosclerotic cardiovascular disease (ASCVD), largely through the release of neutrophil extracellular traps (NETs). These web-like structures, composed of decondensed chromatin, citrullinated histones (e.g., H3), and granular proteins such as neutrophil elastase (NE) and myeloperoxidase (MPO), are generated via a regulated form of cell death termed NETosis. This review aims to systematically synthesize contemporary understanding of the molecular composition and regulatory mechanisms governing NET formation. Furthermore, it seeks to elucidate the multifaceted and stage-specific pathogenic roles of NETs throughout the initiation, progression, and thrombotic complications of atherosclerosis. Finally, the review critically assesses the emerging diagnostic and therapeutic potential of targeting NETs in atherothrombosis. NET formation is driven by multiple synergistic pathways. Central mechanisms include activation of the NADPH oxidase/reactive oxygen species (ROS) axis, engagement of pattern recognition receptors (e.g., TLR2/4) by oxidized low-density lipoprotein (oxLDL), NLRP3 inflammasome activation, and mitochondrial dysfunction involving mitochondrial DNA (mtDNA) release and subsequent cGAS-STING pathway stimulation. External cues, such as low shear stress sensed via the Piezo1 mechanoreceptor and extracellular vesicles carrying oxidative epitopes (e.g., malondialdehyde) from ruptured plaques, further potentiate NETosis. Several cardiovascular risk factors—including dyslipidemia, hyperglycemia, specific genetic variants, and environmental exposures—have been shown to upregulate NET formation, thereby accelerating atherosclerotic pathogenesis. During plaque initiation, NETs exacerbate endothelial injury through the release of cytotoxic histones and proteases, promoting LDL oxidation to pro-inflammatory oxLDL and amplifying early inflammatory cascades. This is achieved partly by activating interferon responses in plasmacytoid dendritic cells and the NLRP3 inflammasome in macrophages, thereby facilitating monocyte recruitment and foam cell formation. In the progression phase, NETs contribute to plaque growth and destabilization. They promote phenotypic switching of vascular smooth muscle cells toward a pro-inflammatory, migratory state. Additionally, NET components, particularly citrullinated histone H3, induce macrophage pyroptosis via both caspase-1/GSDMD and caspase-3/GSDME pathways. This highly inflammatory form of cell death expands the necrotic core and sustains a vicious cycle of inflammation within the evolving plaque. At the complication stage, NETs directly precipitate plaque rupture and acute thrombosis. They degrade the extracellular matrix and thin the fibrous cap by secreting matrix metalloproteinases and inducing vascular smooth muscle cell death. Furthermore, NETs establish a potent prothrombotic milieu: their DNA and histones activate platelets, provide a scaffold for trapping circulating blood cells, concurrently activate the intrinsic and extrinsic coagulation pathways, and impair endogenous fibrinolysis. The clinical relevance of NETs is underscored by their promise as biomarkers. Circulating components such as dsDNA, MPO-DNA complexes, and citrullinated histone H3 correlate with disease severity, plaque vulnerability, and thrombotic risk. Therapeutically, strategies are evolving along two fronts: inhibiting NET formation and clearing existing NETs. Promising approaches include PAD4 inhibitors, NLRP3 inflammasome blockers, DNase I to digest NET scaffolds, and histone-neutralizing antibodies. Notably, several compounds derived from traditional Chinese medicine—such as Paeonol and Guizhi Tongluo Tablets—have demonstrated efficacy in inhibiting NETosis and mitigating atherosclerosis in preclinical models, offering novel multi-target interventional perspectives. In conclusion, NETs represent a critical effector mechanism linking innate immunity, chronic inflammation, and thrombosis in atherosclerosis. Their dynamic involvement across the disease continuum highlights their dual utility as promising biomarkers and therapeutic targets. Future research should prioritize several key areas: elucidating the crosstalk between NETs and other immune cells within the plaque microenvironment; developing selective NETosis inhibitors that preserve essential host-defense functions; validating NET-based biomarker panels in large-scale clinical cohorts for improved risk stratification; exploring combinatorial regimens that integrate NET-targeted therapies with established pharmacological agents; and investigating the specific role of NETs in distinct clinical phenotypes of atherosclerosis to pave the way for personalized treatment strategies in ASCVD.
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