Neutrophil extracellular traps drive immunoinflammatory remodeling in abdominal aortic aneurysm: from inflammatory...

Abdominal aortic aneurysm (AAA) is a chronic vascular disorder characterized by progressive aortic wall dilation, extracellular matrix degradation, and an increased risk of catastrophic rupture. Currently, no effective pharmacological therapy is available to prevent or slow AAA progression. Neutrophil extracellular traps (NETs) have emerged as a critical pathological platform linking dysregulated innate immunity to vascular structural deterioration. In the AAA microenvironment, local inflammation, oxidative stress, metabolic disturbances, altered mechanical forces, and platelet activation collectively contribute to the induction of NETosis. Persistent NET formation promotes immunoinflammatory remodeling of the aortic wall by activating inflammatory sensing pathways, including TLR9, cGAS-STING, and NLRP3, modulating macrophage responses, inducing vascular smooth muscle cell ferroptosis and phenotypic switching, and exacerbating proteolytic degradation, oxidative injury, and immunothrombotic responses. During disease progression, NETs may transition from early drivers of inflammatory amplification to sustained regulators of vascular remodeling, while in advanced AAA they may synergize with intraluminal thrombus formation and structural destabilization to accelerate disease progression. Circulating NET-associated biomarkers represent promising candidates for complementing conventional imaging-based risk assessment; however, their specificity and predictive value require further validation. Therapeutic strategies targeting PAD4-mediated NET formation, the oxidative metabolic environment, NET-associated effector molecules, DNase I-mediated NET degradation, and nucleic acid sensing pathways have demonstrated potential in preclinical studies. This review systematically summarizes the emerging roles of NETs in AAA pathogenesis and discusses future precision strategies integrating biomarkers, multi-omics profiling, and imaging-based risk stratification with stage-specific therapeutic interventions.