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Previous studies have demonstrated that sialylated immunoglobulin G (SIA-IgG) is up-regulated in a variety of epithelial-derived tumors and plays an important biological role. However, the function of SIA-IgG in OSCC progression is yet to be clarified. The expression characteristics and clinical significance of SIA-IgG were investigated using immunohistochemistry, western blot, and bioinformatics analysis. The biological functions of SIA-IgG were evaluated in\u00a0vitro and in\u00a0vivo. The underlying mechanisms of SIA-IgG in OSCC were elucidated using immunoprecipitation, mass spectrometry, and proteomic profiling. Furthermore, we explored the inhibitory effects of an exogenously added SIA-IgG-specific monoclonal antibody, RP215, on OSCC. An elevated level of SIA-IgG was observed in OSCC, and this was linked to poor survival among OSCC patients. Meanwhile, the up-regulation of SIA-IgG and valosin-containing protein (VCP) promoted the malignant progression of OSCC by activating the oxidative phosphorylation pathway. Moreover, SIA-IgG showed potential as a marker of OSCC cancer stem cells. Mechanistically, SIA-IgG enhanced the interaction between VCP and NADH:ubiquinone oxidoreductase subunit B6 (NDUFB6), thereby inhibiting the ubiquitin\u2013proteasome-pathway-mediated degradation of NDUFB6 and sustaining the activation of the oxidative phosphorylation pathway. This inhibitory effect was abrogated by the overexpression of VCP. Furthermore, the SIA-IgG-specific antibody RP215 suppressed the malignant progression of OSCC, both in\u00a0vitro and in\u00a0vivo.<\/jats:p>","DOI":"10.34133\/research.0985","type":"journal-article","created":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T22:19:21Z","timestamp":1760912361000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["Sialylated Immunoglobulin G Promotes the Malignant Progression of Oral Squamous Cell Carcinoma through VCP-Mediated NDUFB6 Stabilization Regulated Mitochondrial Oxidative Phosphorylation"],"prefix":"10.34133","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8572-4881","authenticated-orcid":false,"given":"Lin","family":"Qiu","sequence":"first","affiliation":[{"name":"Central Laboratory, \rPeking University School and Hospital of Stomatology &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China."},{"name":"Department of Oral and Maxillofacial Surgery, \rPeking University School and Hospital of Stomatology &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anqi","family":"Tao","sequence":"additional","affiliation":[{"name":"Central Laboratory, \rPeking University School and Hospital of Stomatology &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China."},{"name":"Department of Periodontology, \rPeking University School and Hospital of Stomatology &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linlin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Central Laboratory, \rPeking University School and Hospital of Stomatology &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiheng","family":"Liao","sequence":"additional","affiliation":[{"name":"Central Laboratory, \rPeking University School and Hospital of Stomatology &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, \rStomatology College of Jiamusi University, Jiamusi, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology, Beijing, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuiying","family":"Li","sequence":"additional","affiliation":[{"name":"Central Laboratory, \rPeking University School and Hospital of Stomatology &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"issue":"9","key":"e_1_3_4_3_2","first-page":"11884","article-title":"Essentials of oral cancer","volume":"8","author":"Rivera C","year":"2015","unstructured":"Rivera C. 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