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Ferroptosis, an iron-dependent form of programmed cell death, has emerged as a potential therapeutic target. However, the regulatory mechanisms that allow CRC cells to evade ferroptosis are not fully understood. This study focuses on OTUB2, a deubiquitinating enzyme, and its role in stabilizing U2AF2, which allows CRC cells to resist ferroptosis and autophagy. We analyzed CRC cells and clinical samples to evaluate the effects of OTUB2 on U2AF2 deubiquitination. OTUB2 knockdown and overexpression models were established in CRC cell lines (LoVo, RKO, SW480, HT115) to assess ferroptosis and autophagy activity. Various assays, including western blotting, immunoprecipitation, colony formation, and transwell migration assays, were used to evaluate cell proliferation, migration, and iron metabolism markers. In vivo xenograft models were also employed to assess tumor growth under OTUB2-U2AF2 axis disruption. OTUB2 was highly expressed in CRC tissues compared to normal controls. Knockdown of OTUB2 significantly increased ferroptosis, while enhancing autophagy. Conversely, OTUB2 overexpression reduced ferroptosis and autophagy, maintaining CRC cell survival and proliferation. In vivo studies confirmed that disrupting the OTUB2-U2AF2 axis impaired tumor growth by activating both ferroptosis and autophagy. Importantly, a reciprocal activation relationship between ferroptosis and autophagy was observed under OTUB2-U2AF2 axis deficiency. OTUB2 stabilizes U2AF2 in CRC cells, enabling them to evade ferroptosis and autophagy. Disruption of the OTUB2-U2AF2 axis activates both processes, suppressing tumor growth. Targeting this axis presents a promising therapeutic strategy for CRC treatment.<\/jats:p>","DOI":"10.1038\/s41419-026-08415-8","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T14:35:47Z","timestamp":1778164547000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["OTUB2-mediated deubiquitination upregulates U2AF2 to promote colorectal cancer evasion of autophagy-ferroptosis"],"prefix":"10.1038","volume":"17","author":[{"given":"Xi","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxin","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qigang","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6977-7131","authenticated-orcid":false,"given":"Ao","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"8415_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.65","volume":"1","author":"EJ Kuipers","year":"2015","unstructured":"Kuipers EJ, Grady WM, Lieberman D, Seufferlein T, Sung JJ, Boelens PG, et al. 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The storage, analysis, and disposal of these samples were conducted in compliance with the guidelines approved by the Ethics Committee of First Affiliated Hospital of University of Science and Technology of China. All animal procedures were performed following NIH guidelines and were approved by the Clinical Medical Ethics Committee of First Affiliated Hospital of University of Science and Technology of China.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"607"}}