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Recently, the targeted therapies, such as Pemigatinib and Ivosidenib, have provided new treatment options for patients carrying fibroblast growth factor receptor (FGFR) and isocitrate dehydrogenase 1\/2 (IDH1\/2) mutations, but only ~30% of patients harbor these mutants; it is urgent to explore novel targets and therapeutic therapies. The frequent downregulation of BAP1 has been observed in CCA, and the low expression of BAP1 is closely related to the poor prognosis of CCA. However, there are no effective interventions to re\u2010activate BAP1 protein; blocking its degradation may provide a feasible strategy for BAP1\u2010downregulation CCA treatment. In this study, we demonstrated the tumor\u2010suppressive roles of BAP1 in CCA and identified VCP functions as the key upstream regulator mediated by BAP1 protein homeostasis. Mechanistically, VCP binds to BAP1 and promotes the latter's ubiquitination degradation via the ubiquitin\u2010proteasome pathway, thus promoting cell proliferation and inhibiting cell apoptosis. Moreover, we found that VCP inhibitors inhibited CCA cell growth and promoted cell apoptosis by blocking BAP1 ubiquitination degradation. Collectively, our findings not only provided a novel mechanism underlying the aberrant low expression of BAP1 in CCA but also verified the anti\u2010tumor effect of VCP inhibitors in CCA, offering a novel therapeutic target for CCA treatment.<\/jats:p>","DOI":"10.1111\/cas.70061","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T01:59:36Z","timestamp":1742781576000},"page":"1579-1591","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["VCP Promotes Cholangiocarcinoma Development by Mediating BAP1 Ubiquitination\u2010Dependent Degradation"],"prefix":"10.1111","volume":"116","author":[{"given":"Peiying","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Pharmacology &amp; Toxicology, Zhejiang Province Key Laboratory of Anti\u2010Cancer Drug Research, College of Pharmaceutical Sciences Zhejiang University  Hangzhou 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