Atherosclerosis is a chronic inflammatory disease initiated by endothelial dysfunction. Junctional adhesion molecule-like protein (JAML) is known to regulate inflammatory responses; however, its function in vascular endothelial cells and atherosclerosis remains unclear. This study aimed to investigate the function of endothelial JAML in atherosclerosis and to uncover the molecular mechanisms involved. We generated mice with specific deletion of JAML in endothelial cells and fed them a high-fat diet to induce atherosclerosis, then assessed plaque formation in the aortic root and entire aorta. In parallel, endothelial cells were treated with tumor necrosis factor alpha, and the effects of increasing or silencing JAML on adhesion molecule expression were evaluated, with protein interactions analyzed by co-immunoprecipitation and immunoblotting. JAML exhibited downregulation in endothelial cells within both atherosclerotic lesions and cultured cells subjected to inflammatory stimuli. In mice, the loss of JAML resulted in exacerbated atherosclerotic progression, characterized by larger plaque formation, increased vascular inflammation, and increased macrophage infiltration. Conversely, overexpression of JAML attenuated the expression of adhesion molecules. Mechanistically, JAML was found to promote the degradation of signal transducer and activator of transcription 1 (STAT1) by facilitating its interaction with the E3 ubiquitin ligase tripartite motif-containing 25. This interaction led to ubiquitin-mediated proteolysis of STAT1, independent of alterations in its gene expression levels. These findings suggest that endothelial JAML holds significant promise as a novel therapeutic target for the prevention and intervention of atherosclerosis.

A disintegrin and metalloproteinase 9 (ADAM9), a member of the ADAM family, is expressed across multiple organs and is crucial to multiple physiological processes. Increasing evidence implicates ADAM9 in cancer progression through extracellular matrix (ECM) remodeling, protein shedding, and tumor microenvironment modulation. This study comprehensively reviews the literature on the clinical significance of ADAM9 and the mechanistic roles of ADAM9 in cancer. The results of our pan-cancer analysis demonstrated that ADAM9 is frequently upregulated and consistently associated with poor prognosis across tumor types. The results of in silico analyses also revealed that increased ADAM9 expression is correlated with an immunosuppressive tumor microenvironment and the activation of cancer-promoting pathways, such as cell cycle progression, epithelial-mesenchymal transition (EMT), and metabolism. This study also reviewed therapeutic strategies targeting ADAM9 and evaluated their potential in cancer treatment. This review provides insights into ADAM9 as both a biomarker of malignancy and a promising therapeutic target.