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aortic medial degeneration characterized by glycan-rich matrix accumulation. Marfan syndrome (MFS) is the most common inherited connective tissue disorder associated with TAAD. Although vascular smooth muscle cell metabolic dysfunction has emerged as a pathogenic driver of TAAD, surgical repair remains the mainstay of treatment. This study aimed to investigate the role of the hexosamine biosynthetic pathway (HBP) in sporadic and genetic TAAD pathophysiology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Hexosamine biosynthetic pathway activation was analysed in aortas from an MFS mouse model, a \u03b2-aminopropionitrile-induced non-genetic TAAD model, and patients with sporadic TAAD using transcriptomic and metabolomic approaches. Aortic dilatation was monitored by ultrasound imaging. Pharmacological inhibition of HBP and integrated stress response (ISR) was performed to assess their therapeutic potential.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Hexosamine biosynthetic pathway was up-regulated in both an MFS mouse model and \u03b2-aminopropionitrile-induced TAAD, as well as in aortic samples from MFS and sporadic TAAD patients. Enhanced HBP activity contributed to aortic dilatation and medial degeneration via vascular smooth muscle cell dysfunction and ISR activation. Inhibition of HBP or ISR reversed these effects in the MFS model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The HBP\u2013ISR axis drives medial degeneration in TAAD. These findings identify HBP and ISR as a potential target in TAAD of both genetic and non-genetic origin.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaf556","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T10:03:18Z","timestamp":1752746598000},"page":"4988-5005","source":"Crossref","is-referenced-by-count":9,"title":["Excessive glycosylation drives thoracic aortic aneurysm formation through integrated stress response"],"prefix":"10.1093","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1456-2946","authenticated-orcid":false,"given":"Antonio","family":"Rochano-Ortiz","sequence":"first","affiliation":[{"name":"Laboratory of Vascular Pathology, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM) , 28040 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8753-6796","authenticated-orcid":false,"given":"Irene","family":"San Sebasti\u00e1n-Jaraba","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM) , 28040 Madrid ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3616-6734","authenticated-orcid":false,"given":"Carmen","family":"Zamora","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM) , 28040 Madrid ,","place":["Spain"]},{"name":"Department of Cardiac Surgery, University Hospital Puerta de Hierro, Majadahonda , Majadahonda ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7140-0795","authenticated-orcid":false,"given":"Carolina","family":"Sim\u00f3","sequence":"additional","affiliation":[{"name":"Molecular Nutrition and Metabolism, Institute of Food Science Research (CIAL, CSIC-UAM) , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6728-4325","authenticated-orcid":false,"given":"Virginia","family":"Garc\u00eda-Ca\u00f1as","sequence":"additional","affiliation":[{"name":"Molecular Nutrition and Metabolism, Institute of Food Science Research (CIAL, CSIC-UAM) , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8495-6051","authenticated-orcid":false,"given":"Sacramento","family":"Mart\u00ednez-Albaladejo","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM) , 28040 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Fern\u00e1ndez-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM) , 28040 Madrid 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