{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:59:52Z","timestamp":1790315992384,"version":"4.1.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Oral squamous cell carcinoma (OSCC) lacks practical and non-invasive biomarkers for case detection. Saliva is an attractive source for biomarker discovery; however, many reported candidates lack support from independent biological data layers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed untargeted salivary metabolomics in 40 patients with OSCC and 40 healthy controls. Differential metabolites were identified using multivariate and univariate analyses. Candidate diagnostic metabolites were prioritized by support vector machine-recursive feature elimination, random forest, and receiver operating characteristic (ROC) analyses. The biological context of the salivary findings was further examined using two GEO transcriptomic cohorts, the TCGA-HNSC cohort, a single-cell RNA sequencing dataset, and public protein-level resources including the Human Protein Atlas and CPTAC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>OSCC and control samples showed distinct salivary metabolic profiles, and 19 annotated endogenous differential metabolites were retained for downstream analysis. These alterations were mainly enriched in amino acid- and lipid-related pathways, including arginine and proline metabolism. Within the discovery cohort, internal cross-validation and feature ranking converged on a seven-metabolite panel; however, because feature selection and evaluation were performed on the same 80 samples without nested cross-validation, performance estimates are subject to optimism bias and are not reported here as validated diagnostic metrics. In GSE6631 and GSE37991 showed concordant downregulation of linoleic acid metabolism, arachidonic acid metabolism, bile acid-related programs, fatty acid metabolism, and peroxisome pathways in tumor tissue. Single-cell analysis further suggested reduced activity of curated metabolic modules in malignant cells and tumor-associated tissue states, though these comparisons did not account for patient-level dependence. At the protein level, ALDH1A1 and VDR were decreased, whereas SLC7A11 was increased in tumor tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>OSCC was associated with a saliva-derived metabolic signature supported by pathway-level concordance across multiple public data layers. The overall pattern suggests lipid remodeling, reduced bile acid-related signaling, altered amino acid metabolism, and enhanced redox defense. These findings support further targeted quantification and external validation of saliva-based biomarker candidates for OSCC, while the current panel should be regarded as a preliminary discovery-set candidate signature.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1901210","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:31:58Z","timestamp":1790314318000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A saliva-derived metabolic signature with multi-omics support for oral squamous cell carcinoma diagnosis"],"prefix":"10.3389","volume":"14","author":[{"given":"Hongyu","family":"Zheng","sequence":"first","affiliation":[{"name":"National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]},{"name":"Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuijuan","family":"Hu","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingping","family":"Tian","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xu","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqing","family":"Ma","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]},{"name":"Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuelian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam and University of Amsterdam","place":["Amsterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitong","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]},{"name":"Department of Oral and Maxillofacial Head and Neck Oncology, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Sun","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]},{"name":"Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"111697","DOI":"10.1016\/j.celrep.2022.111697","article-title":"Systematic single-cell pathway analysis to characterize early T cell activation","volume":"41","author":"Bibby","year":"2022","journal-title":"Cell Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1016\/j.devcel.2021.04.013","article-title":"Lipid metabolism in cancer: new perspectives and emerging mechanisms","volume":"56","author":"Broadfield","year":"2021","journal-title":"Dev. Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1038\/nature14129","article-title":"Comprehensive genomic characterization of head and neck squamous cell carcinomas","volume":"517","author":"Cancer Genome Atlas","year":"2015","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/s41419-024-06759-7","article-title":"The enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of oral squamous cell carcinoma","volume":"15","author":"Cheng","year":"2024","journal-title":"Cell Death Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1056\/nejmra1715715","article-title":"Head and neck cancer","volume":"382","author":"Chow","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1186\/s13046-024-03141-5","article-title":"Connecting the dots: investigating the link between environmental, genetic, and epigenetic influences in metabolomic alterations in oral squamous cell carcinoma","volume":"43","author":"Gupta","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"4125","DOI":"10.3390\/cancers13164125","article-title":"Fatty acid receptor CD36 functions as a surrogate parameter for lymph node metastasis in oral squamous cell carcinoma","volume":"13","author":"Haidari","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1111\/odi.14150","article-title":"Tyrosine sulphation of CXCR4 induces the migration of fibroblast in OSF","volume":"29","author":"He","year":"2023","journal-title":"Oral Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.aca.2018.10.070","article-title":"Integrated analyses utilizing metabolomics and transcriptomics reveal perturbation of the polyamine pathway in oral cavity squamous cell carcinoma","volume":"1050","author":"Hsu","year":"2019","journal-title":"Anal. Chim. Acta"},{"key":"B11","doi-asserted-by":"publisher","first-page":"31520","DOI":"10.1038\/srep31520","article-title":"Identification of salivary metabolomic biomarkers for oral cancer screening","volume":"6","author":"Ishikawa","year":"2016","journal-title":"Sci. Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"Johnson","year":"2020","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B13","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.jdsr.2023.12.004","article-title":"Adjunctive aids for the detection of oral squamous cell carcinoma and oral potentially malignant disorders: a systematic review of systematic reviews","volume":"60","author":"Lau","year":"2024","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.3892\/ol.2015.3542","article-title":"Expression of ALDH1A1 and CD44 in primary head and neck squamous cell carcinoma and their value for carcinogenesis, tumor progression and cancer stem cell identification","volume":"10","author":"Leinung","year":"2015","journal-title":"Oncol. Lett."},{"key":"B15","doi-asserted-by":"publisher","first-page":"6068","DOI":"10.3390\/cancers13236068","article-title":"The role of arginine metabolism in oral tongue squamous cell carcinoma","volume":"13","author":"Leung","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"8442","DOI":"10.1158\/1078-0432.CCR-04-1167","article-title":"Salivary transcriptome diagnostics for oral cancer detection","volume":"10","author":"Li","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"76","DOI":"10.7150\/jca.59777","article-title":"Metabolomics based plasma biomarkers for diagnosis of oral squamous cell carcinoma and oral erosive Lichen planus","volume":"13","author":"Li","year":"2022","journal-title":"J. Cancer"},{"key":"B18","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/s12276-020-0375-3","article-title":"Amino acids in cancer","volume":"52","author":"Lieu","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"S204","DOI":"10.4103\/jpbs.jpbs_593_25","article-title":"A narrative review on oral squamous cell carcinoma","volume":"17","author":"Muralidharan","year":"2025","journal-title":"J. Pharm. Bioallied Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"109305","DOI":"10.1016\/j.identj.2025.109305","article-title":"Expression analysis, diagnostic and prognostic accuracy of microRNAs in oral cancer: an overview with meta-analysis","volume":"76","author":"Nair","year":"2026","journal-title":"Int. Dent. J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1111\/j.1749-6632.1993.tb18343.x","article-title":"Methods for collecting saliva","volume":"694","author":"Navazesh","year":"1993","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1007\/s00784-023-05481-6","article-title":"Salivary metabolomics in oral potentially malignant disorders and oral cancer patients-a systematic review with meta-analysis","volume":"28","author":"Nazar","year":"2024","journal-title":"Clin. Oral Investig."},{"key":"B23","doi-asserted-by":"publisher","first-page":"294","DOI":"10.3390\/metabo12040294","article-title":"Salivary metabolomics for oral squamous cell carcinoma diagnosis: a systematic review","volume":"12","author":"Nijakowski","year":"2022","journal-title":"Metabolites"},{"key":"B24","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cmet.2015.12.006","article-title":"The emerging hallmarks of cancer metabolism","volume":"23","author":"Pavlova","year":"2016","journal-title":"Cell Metab."},{"key":"B25","doi-asserted-by":"publisher","first-page":"6097","DOI":"10.1007\/s00432-023-04572-x","article-title":"Integration of transcriptomics and metabolomics reveals a novel gene signature guided by FN1 associated with immune response in oral squamous cell carcinoma tumorigenesis","volume":"149","author":"Peng","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1016\/j.cell.2017.10.044","article-title":"Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer","volume":"171","author":"Puram","year":"2017","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/s41420-024-02023-1","article-title":"The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma","volume":"10","author":"Schwarcz","year":"2024","journal-title":"Cell Death Discov."},{"key":"B28","doi-asserted-by":"publisher","first-page":"16167","DOI":"10.1073\/pnas.2001395117","article-title":"Oral squamous cell carcinoma diagnosed from saliva metabolic profiling","volume":"117","author":"Song","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B29","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1111\/j.1365-2125.1976.tb00609.x","article-title":"Methods for collecting individual components of mixed saliva: the relevance to clinical pharmacology","volume":"3","author":"Stephen","year":"1976","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1007\/s11306-009-0178-y","article-title":"Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles","volume":"6","author":"Sugimoto","year":"2010","journal-title":"Metabolomics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1432520","DOI":"10.3389\/fphar.2024.1432520","article-title":"Circ-CDK8 regulates SLC7A11-mediated ferroptosis by inhibiting miR-615-5p to promote progression in oral squamous cell carcinomas","volume":"15","author":"Sun","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"B33","doi-asserted-by":"publisher","first-page":"400","DOI":"10.3390\/biom12030400","article-title":"Identification of metabolism-associated biomarkers for early and precise diagnosis of oral squamous cell carcinoma","volume":"12","author":"Wang","year":"2022","journal-title":"Biomolecules"},{"key":"B34","doi-asserted-by":"publisher","first-page":"19S","DOI":"10.14219\/jada.archive.2012.0339","article-title":"Salivaomics","volume":"143","author":"Wong","year":"2012","journal-title":"J. Am. Dent. Assoc."},{"key":"B35","doi-asserted-by":"publisher","first-page":"426","DOI":"10.3389\/fonc.2020.00426","article-title":"Integrated non-targeted and targeted metabolomics uncovers amino acid markers of oral squamous cell carcinoma","volume":"10","author":"Yang","year":"2020","journal-title":"Front. Oncol."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1901210\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:32:00Z","timestamp":1790314320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1901210\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":35,"alternative-id":["10.3389\/fcell.2026.1901210"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1901210","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"article-number":"1901210"}}