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However, its specific role in hepatocellular carcinoma (HCC) progression and drug resistance remains unclear. This study revealed that CUL4B is upregulated in HCC tissues, with elevated levels correlating with poor patient prognosis. A strong inverse relationship was observed between the expression of CUL4B and the tumor suppressor miR-143-3p in human HCC samples; CUL4B knockdown significantly increased miR-143-3p levels. Moreover, suppression of CUL4B inhibited HCC cell proliferation and enhanced sensitivity to oxaliplatin through miR-143-3p upregulation. Fused in sarcoma (FUS), an RNA-binding protein implicated in miRNA biogenesis, was identified as a novel CRL4B\n                    <jats:sup>DTL<\/jats:sup>\n                    substrate. CUL4B facilitates FUS ubiquitination and subsequent degradation, thereby reducing FUS protein levels. This reduction impairs miR-143-3p formation, activates the KRAS signaling pathway, and promotes tumor progression and oxaliplatin resistance. In summary, this study provided compelling evidence that CUL4B knockdown may be a promising strategy for treating HCC and increasing tumor cell sensitivity to oxaliplatin therapy.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08320-6","type":"journal-article","created":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T05:16:10Z","timestamp":1765689370000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CUL4B promotes hepatocellular carcinoma progression and oxaliplatin resistance by facilitating FUS degradation"],"prefix":"10.1038","volume":"17","author":[{"given":"Jun-Dong","family":"Wei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinle","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yetian","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangyang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3776-1818","authenticated-orcid":false,"given":"Xingang","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2865-5311","authenticated-orcid":false,"given":"Hui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7038-4984","authenticated-orcid":false,"given":"Lisha","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,14]]},"reference":[{"key":"8320_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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All animal experiments were approved by the Taizhou University Institutional Animal Care and Use Committee (approval no. TZXY-2024-20241161), and the use of human HCC tissues and patient information was approved by the Ethics Committee of Shanghai Outdo Biotech Company (approval no. SHYJS-CP-1701002). Informed consent was obtained from all human participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"116"}}