JCAD/KIAA1462: biology, pathophysiology, and translational perspectives in vascular disease

Junctional cadherin 5-associated protein (JCAD/KIAA1462) is an endothelial junctional protein encoded by a locus robustly associated with coronary artery disease and myocardial infarction in genome-wide association studies. Initially identified as a structural component of endothelial cell-cell junctions, JCAD has since emerged as a mechanosensor and regulator of key intracellular pathways (i.e. Hippo/YAP, PI3 K/Akt, and MAPK/ERK) with functional consequences for endothelial homeostasis, inflammation, and vascular tone. In this review, we summarise the current understanding of JCAD biology, from its molecular features and pathway interactions to its experimental roles in atherosclerosis, arterial thrombosis, and ischaemic stroke. We further discuss emerging translational evidence suggesting circulating JCAD as an independent predictor of adverse cardiovascular events in patients with acute coronary syndromes, and its prognostic potential in ischaemic stroke. The review also addresses the expanding biology of JCAD within the cardiovascular system, hypothesizing links to conditions such as hypertension, heart failure with preserved ejection fraction, and calcific aortic valve disease, as well as key limitations and therapeutic challenges. Overall, the available evidence highlights JCAD as a biologically plausible and potentially clinically relevant endothelial mediator, though independent validation and substantial mechanistic work remain necessary before its translational potential can be fully realized.