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Initially identified as a structural component of endothelial cell\u2013cell junctions, JCAD has since emerged as a mechanosensor and regulator of key intracellular pathways (i.e. Hippo\/YAP, PI3K\/Akt, and mitogen-activated protein kinase\/extracellular signal-regulated kinase) with functional consequences for endothelial homeostasis, inflammation, and vascular tone. In this review, we summarize 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.<\/jats:p>","DOI":"10.1093\/cvr\/cvag182","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T11:22:24Z","timestamp":1787570544000},"page":"2070-2078","source":"Crossref","is-referenced-by-count":0,"title":["JCAD\/KIAA1462: biology, pathophysiology, and translational perspectives in vascular disease"],"prefix":"10.1093","volume":"122","author":[{"given":"Margherita","family":"Moriero","sequence":"first","affiliation":[{"name":"First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa , 6 viale Benedetto XV, Genoa 16132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8245-7287","authenticated-orcid":false,"given":"Simon","family":"Kraler","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, University of Z\u00fcrich , Schlieren ,","place":["Switzerland"]},{"name":"Department of Cardiology, University Hospital of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amedeo","family":"Tirandi","sequence":"additional","affiliation":[{"name":"First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa , 6 viale Benedetto XV, Genoa 16132 ,","place":["Italy"]},{"name":"Center for Molecular Cardiology, University of Z\u00fcrich , Schlieren ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Di Vece","sequence":"additional","affiliation":[{"name":"First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa , 6 viale Benedetto XV, Genoa 16132 ,","place":["Italy"]},{"name":"Department of Internal Medicine B, University Medicine Greifswald , Greifswald ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F","family":"Luscher","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, University of Z\u00fcrich , Schlieren ,","place":["Switzerland"]},{"name":"Royal Brompton and Harefield Hospitals and Imperial College , London ,","place":["UK"]},{"name":"School of Cardiovascular Medicine and Sciences, Kings College London , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Carbone","sequence":"additional","affiliation":[{"name":"First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa , 6 viale Benedetto XV, Genoa 16132 ,","place":["Italy"]},{"name":"IRCCS Ospedale Policlinico San Martino AOM , Genoa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Ramoni","sequence":"additional","affiliation":[{"name":"First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa , 6 viale Benedetto XV, Genoa 16132 ,","place":["Italy"]},{"name":"IRCCS Ospedale Policlinico San Martino AOM , Genoa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Bonaventura","sequence":"additional","affiliation":[{"name":"Medical Center, S.C. Medicina Generale 1, Ospedale di Circolo and Fondazione Macchi, Department of Internal Medicine, ASST Sette Laghi, Varese ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni G","family":"Camici","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, University of Z\u00fcrich , Schlieren ,","place":["Switzerland"]},{"name":"Department of Research and Education, University Hospital Zurich , Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0823-8729","authenticated-orcid":false,"given":"Fabrizio","family":"Montecucco","sequence":"additional","affiliation":[{"name":"First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa , 6 viale Benedetto XV, Genoa 16132 ,","place":["Italy"]},{"name":"IRCCS Ospedale Policlinico San Martino AOM , Genoa 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