Neutrophil extracellular traps: emerging drivers and therapeutic targets in abdominal aortic aneurysm pathogenesis

Abdominal aortic aneurysm (AAA) is a life-threatening condition with no effective pharmacological treatments, underscoring the critical need to identify novel therapeutic targets. Emerging translational and clinical evidence implicates neutrophil extracellular traps (NETs) as potential drivers of AAA pathogenesis. This review systematically delineates the mechanisms by which NETs contribute to aortic wall degradation, focusing on their direct cytotoxicity to vascular smooth muscle cells (VSMCs), induction of VSMC phenotypic switching and ferroptosis, amplification of inflammatory cascades, and propagation of thromboinflammation. Key mediators include PAD4, IL-1β, PI3Kγ, neutrophil elastase, myeloperoxidase, and mitochondrial DNA. NET components (citrullinated histone H3, cell-free DNA, neutrophil elastase) serve as promising diagnostic and prognostic biomarkers. Preclinical studies highlight the efficacy of NET-targeting strategies, including inhibiting NET formation, degrading existing NETs, neutralizing cytotoxic components, and modulating downstream pathways (e.g., with ferroptosis inhibitors). Nanotechnology platforms enhance site-specific delivery of these agents. By integrating the research background with its practical implications, we conclude that targeting NETs represents a promising paradigm shift. Despite translational challenges, this approach offers a rational framework for developing the first pharmacotherapies aimed at stabilizing AAA and addressing a major unmet clinical need.