Abstract
OBJECTIVE: This systematic review aimed to comprehensively evaluate the current evidence linking cluster of differentiation 40 and its ligand (CD40/CD40L) signaling to aneurysm development and progression across different anatomical sites. METHODS: A systematic literature search was performed in PubMed, Embase, Web of Science, and Scopus databases for studies published up to July 27, 2025, according to predefined inclusion criteria. Eligible studies were those that used clinical samples, human tissues, animal models, in vitro experiments, or genetic analyses to directly investigate the role of CD40/CD40L signaling in aneurysmal disease. Data extraction was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Sixteen studies met the inclusion criteria. The findings consistently demonstrated robust upregulation of CD40 and CD40L within aneurysmal walls. Circulating soluble CD40L levels were significantly elevated in patients with thoracic aortic aneurysms and ruptured intracranial aneurysms. In contrast, results in abdominal aortic aneurysm cases were variable. Genetic analyses indicated that lifelong genetically elevated CD40 expression was associated with a lower risk of aortic aneurysm. Mechanistic studies revealed that CD40/CD40L signaling promoted endothelial activation, immune cell recruitment, pro-inflammatory cytokine and chemokine release, and extracellular matrix degradation. In murine models, CD40L deficiency markedly reduced aneurysm incidence, dilation, and rupture, confirming a causal relationship. Therapeutic blockade of the CD40/CD40L axis significantly attenuated aneurysm formation in experimental models, underscoring its translational potential. CONCLUSION: The CD40/CD40L signaling pathway plays a pivotal role in aneurysm pathogenesis by amplifying vascular inflammation and promoting matrix remodeling. Targeting this pathway demonstrates promising efficacy in preclinical studies and warrants further investigation for potential clinical application.