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Therapies for OSCC are improving, but radiotherapy resistance remains a major clinical challenge. Here, we found that the S-phase kinase-associated protein 2 (Skp2) is overexpressed in OSCC cells and tissues. Knockdown of Skp2 significantly increased the radiotherapy sensitivity of OSCC cells. Further potential mechanisms suggest that Skp2-deficient restoration of radiotherapy sensitivity in OSCC cells may induce intrinsic apoptosis through inhibition of the Akt\/Wee1\/CDK1 axis, which inhibits Survivin phosphorylation and promotes its ubiquitination and degradation by FBXL7. Clinicopathologic histological analysis showed that Skp2 was positively correlated with the expression of p-Akt and Survivin in OSCC tissues. Furthermore, knockdown or inhibition of Skp2 overcame the radiotherapy resistance of OSCC cells. In conclusion, our study demonstrated that targeting the Skp2-Survivin axis could serve as an attractive and promising potential therapeutic target for radiotherapy sensitization in OSCC.<\/jats:p>","DOI":"10.1038\/s41420-025-02463-3","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T20:10:31Z","timestamp":1744056631000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["E3 ligase Skp2-mediated stabilization of survivin contributes to radioresistance"],"prefix":"10.1038","volume":"11","author":[{"given":"Shiming","family":"Tan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruirui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinglin","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Yi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuangze","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6541-064X","authenticated-orcid":false,"given":"Xiaoying","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Gan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8377-8269","authenticated-orcid":false,"given":"Jinzhuang","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinfang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7267-6494","authenticated-orcid":false,"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"key":"2463_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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