Therapeutic Targeting of Signaling Pathways in Abdominal Aortic Aneurysm: From Pathogenesis to Precision Medicine

Abdominal aortic aneurysms (AAAs) are life-threatening cardiovascular disorders with limited treatment options, largely due to an incomplete understanding of their molecular and cellular pathogenesis. A comprehensive elucidation of the mechanisms driving AAA initiation, progression, and rupture is critical for developing novel therapeutic interventions. Emerging research has highlighted the central role of inflammatory processes in AAA pathophysiology, including dysregulated extracellular matrix (ECM) remodeling, chronic vascular inflammation, immune cell infiltration, and vascular smooth muscle cell (VSMC) dysfunction. These pathological processes are regulated by complex signaling pathways with divergent roles in AAA progression: while NF-κB, MAPK, STAT, and Notch signaling exacerbate disease pathogenesis, AMPK, PPAR-γ, and Nrf2 pathways exert protective effects. Notably, the PI3K/Akt and TGF-β signaling cascades demonstrate context-dependent dual roles, capable of either promoting or inhibiting AAA development. This comprehensive review synthesizes current knowledge of AAA pathophysiology with emphasis on druggable targets within these signaling networks. We critically evaluate emerging therapeutic strategies including miRNA-based interventions, nanoparticle-mediated drug delivery systems, and stem cell therapies that offer promising approaches for precision modulation of disease-specific pathways. By integrating current mechanistic understanding with therapeutic development, this review aims to provide a framework for designing effective pharmacological strategies that could transform AAA management from surgical intervention to medical prevention, addressing a critical unmet clinical need.