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While glycosylation plays a key role in cellular signaling and inflammation, its role in IVD degeneration remains poorly understood. This study characterizes glycan alterations in human healthy and degenerated IVDs using glycomic (UPLC\u2010MS, MALDI\u2010IMS) and proteomic (LC\u2010MS) analyses, combined with functional studies. These results identify hypersialylation, especially \u03b1\u20102,6\u2010linked sialic acid, as a prominent feature of degenerated IVDs. In vitro inhibition of sialylation (3Fax\u2010peracetyl Neu5Ac) in nucleus pulposus cells demonstrates reduced oxidative stress and inflammatory signaling, indicating a functional role for hypersialylation in IVD pathology. Targeting glycosylation pathways, notably sialylation, emerges as a promising therapeutic strategy for IVD degeneration.<\/jats:p>","DOI":"10.1002\/advs.202506669","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T11:56:48Z","timestamp":1763121408000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of Hypersialylation in Human Intervertebral Disc Degeneration Modulates Inflammation and Metabolism"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7752-9784","authenticated-orcid":false,"given":"Kieran","family":"Joyce","sequence":"first","affiliation":[{"name":"C\u00daRAM Research Ireland Centre for Medical Devices Biomedical Sciences Building University of Galway  Galway H91 W2TY Ireland"},{"name":"School of Medicine University of Galway  Galway H91 TK33 Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aert F.","family":"Scheper","sequence":"additional","affiliation":[{"name":"C\u00daRAM Research Ireland Centre for Medical Devices Biomedical Sciences Building University of Galway  Galway H91 W2TY Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aung Myat","family":"Phyo","sequence":"additional","affiliation":[{"name":"C\u00daRAM Research Ireland Centre for Medical Devices Biomedical Sciences Building University of Galway  Galway H91 W2TY Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roisin O\u2019","family":"Flaherty","sequence":"additional","affiliation":[{"name":"Department of Chemistry Maynooth University  Maynooth W23 F2K8 Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Drake","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Pharmacology Medical University of South Carolina  Charleston South Carolina 29425 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiden","family":"Devitt","sequence":"additional","affiliation":[{"name":"School of Medicine University of Galway  Galway H91 TK33 Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Marchetti\u2010Deschmann","sequence":"additional","affiliation":[{"name":"Institute of Chemical Technologies and Analytics  TU Wien Vienna 1060 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radka","family":"Saldova","sequence":"additional","affiliation":[{"name":"C\u00daRAM Research Ireland Centre for Medical Devices Biomedical Sciences Building University of Galway  Galway H91 W2TY Ireland"},{"name":"National Institute for Bioprocessing Research and Training (NIBRT)  Dublin A94 X099 Ireland"},{"name":"School of Medicine College of Health and Agricultural Science University College Dublin  Dublin D04 C1P1 Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6292-4933","authenticated-orcid":false,"given":"Abhay","family":"Pandit","sequence":"additional","affiliation":[{"name":"C\u00daRAM Research Ireland Centre for Medical Devices Biomedical Sciences Building University of Galway  Galway H91 W2TY Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"e_1_2_10_1_1","volume-title":"Essentials of Glycobiology","author":"Varki A.","year":"2022"},{"key":"e_1_2_10_2_1","first-page":"679","volume":"78","author":"Wiederschain G. 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