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In our previous study, we identified for the first time that the family with sequence similarity 83, member A (FAM83A), is overexpressed in HNSCC and associated with poor patient prognosis. However, its role in HNSCC metabolism remains unclear. M2\u2010type pyruvate kinase 2 (PKM2) plays a critical role in glucose metabolic reprogramming in cancer cells, but the regulatory network involving PKM2 and its interaction with FAM83A in HNSCC progression remains poorly understood. In this study, we investigate the relationship between FAM83A and PKM2 in HNSCC for the first time. The overexpression of PKM2 correlates with FAM83A upregulation in HNSCC clinical samples. Single\u2010cell RNA sequencing and RNA sequencing analyses demonstrate that FAM83A enhances the glucose metabolism pathway in HNSCC. In\u00a0vitro, FAM83A promotes glycolytic activity and accelerates lactate production in HNSCC. Inhibition of PKM2 reverses the increased lactate production, migration, invasion, and epithelial\u2010mesenchymal transition (EMT) induced by FAM83A overexpression. Mechanistically, FAM83A promotes the transcriptional activation of PKM2 by activating the Wnt\/\u03b2\u2010catenin signaling pathway. Furthermore, the integration of FAM83A with casein kinase 1 alpha (CK1\u03b1) contributes to the activation of the Wnt\/\u03b2\u2010catenin signaling pathway. Finally, shikonin, a pharmacological inhibitor of PKM2, protects mice from HNSCC progression and metastasis induced by FAM83A in\u00a0vivo. Our findings reveal that PKM2\u2010mediated aerobic glycolysis induced by FAM83A promotes the progression and metastasis of HNSCC, presenting a promising therapeutic target for HNSCC patients.<\/jats:p>","DOI":"10.1096\/fj.202500989rr","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T11:43:41Z","timestamp":1752147821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>FAM83A<\/scp>\n                    Promotes the Progression and Metastasis of Head and Neck Squamous Cell Carcinoma via\n                    <scp>PKM2<\/scp>\n                    \u2010Mediated Aerobic Glycolysis"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1190-5665","authenticated-orcid":false,"given":"Yuyao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endodontics The Affiliated Stomatological Hospital of Nanjing Medical University  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