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This study aimed to explore the role of Fbxo2, a SKP1-Cullin-F-box (SCF) E3 ubiquitin ligase, in PCa progression. Analysis of prostate tissue samples revealed that Fbxo2 is downregulated in PCa, and higher Fbxo2 expression correlates with better patient prognosis. Functional assays conducted both in vitro and in vivo demonstrated that Fbxo2 reduces cell proliferation and metastasis in PCa. Using co-immunoprecipitation mass spectrometry (co-IP-MS), co-IP, western blotting, and ubiquitin assays, we identified that m6A reader YTHDF2, an oncoprotein that is upregulated in PCa, was a substrate of Fbxo2-mediated degradation. Notably, Fbxo2 mutants lacking the C-terminal region were less effective in promoting YTHDF2 ubiquitination and destruction. Furthermore, lysine 286 (K286) of YTHDF2 was identified as the key ubiquitination site. A series of rescue experiments revealed that silencing or overexpressing YTHDF2 modulated the effects of Fbxo2 knockdown or overexpression, confirming their functional interplay. Mechanistically, YTHDF2 enhanced the PCa progression and metastasis by modulating the m6A methylation of\n                    <jats:italic>CDKN1C<\/jats:italic>\n                    mRNA. Together, these findings suggest that Fbxo2 axis may serve as a potential prognostic marker and therapeutic target in PCa.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08396-0","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T19:07:25Z","timestamp":1767035245000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Fbxo2 suppresses prostate cancer progression by regulating YTHDF2 ubiquitination and degradation"],"prefix":"10.1038","volume":"17","author":[{"given":"Xinyu","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangcheng","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Ling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiu","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6465-7779","authenticated-orcid":false,"given":"Zhiwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boxin","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3305-2640","authenticated-orcid":false,"given":"Lixia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"8396_CR1","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1007\/s11912-024-01614-6","volume":"26","author":"MNE Almeeri","year":"2024","unstructured":"Almeeri MNE, Awies M, Constantinou C. 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All animal studies were approved by the Animal Experimentation Ethical Committee of Soochow University (SUDA20230727A07). The protocol for obtaining patient tissue specimens was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University (JD-LK2024142-I01), and written informed consent was obtained from all patients prior to tissue collection.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"153"}}