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Here, we identify RNA\u2010binding motif protein 25 (RBM25) as a potent oncogenic driver that is overexpressed in HCC and correlates with dismal patient prognosis. Functionally, RBM25 depletion impairs HCC progression across in vitro models, in vivo xenografts, and patient\u2010derived organoids. Integrated transcriptomic and interactome profiling reveals that RBM25 orchestrates a specific AS landscape, most notably promoting exon 13 inclusion of MYPT1. Mechanistically, RBM25 recruits PRPF40A to facilitate the production of the oncogenic MYPT1\u2010L isoform. This isoform switch acts as a molecular stabilizer for the transcriptional co\u2010activator YAP, thereby sustaining Hippo pathway dysregulation and tumor growth. Finally, a high\u2010throughput screen of the US drug collection identified candicidin as a small\u2010molecule inhibitor that suppresses RBM25 expression, effectively phenocopying RBM25 knockdown. Our findings define the RBM25\u2010MYPT1\u2010YAP axis as a critical vulnerability in HCC and nominate RBM25 as a viable prognostic biomarker and therapeutic target.<\/jats:p>","DOI":"10.1002\/advs.77792","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:43:54Z","timestamp":1789623834000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RBM25 Drives Hepatocellular Carcinoma Progression by Stabilizing YAP Through Regulating Oncogenic Splicing\u2010switch of MYPT1"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-5886","authenticated-orcid":false,"given":"Wenjing","family":"Zhang","sequence":"first","affiliation":[{"name":"Sino\u2010US Research Center for Cancer Translational Medicine of the Second Affiliated Hospital of Dalian Medical University &amp; Institute of Cancer Stem Cell Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9023-2495","authenticated-orcid":false,"given":"Lili","family":"Zhi","sequence":"additional","affiliation":[{"name":"Sino\u2010US Research Center for Cancer Translational Medicine of the Second Affiliated Hospital of Dalian Medical University &amp; Institute of Cancer Stem Cell Dalian Medical University  Dalian China"},{"name":"Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3368-1919","authenticated-orcid":false,"given":"Tian","family":"Huang","sequence":"additional","affiliation":[{"name":"Sino\u2010US Research Center for Cancer Translational Medicine of the Second Affiliated Hospital of Dalian Medical University &amp; Institute of Cancer Stem Cell Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingya","family":"Feng","sequence":"additional","affiliation":[{"name":"Sino\u2010US Research Center for Cancer Translational Medicine of the Second Affiliated Hospital of Dalian Medical University &amp; Institute of Cancer Stem Cell Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoqun","family":"Chen","sequence":"additional","affiliation":[{"name":"Sino\u2010US Research Center for Cancer Translational Medicine of the Second Affiliated Hospital of Dalian Medical University &amp; Institute of Cancer Stem Cell Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6481-5407","authenticated-orcid":false,"given":"Huanhuan","family":"Wei","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Computational Biology Bio\u2010Med Big Data Center Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Liu","sequence":"additional","affiliation":[{"name":"Sino\u2010US Research Center for Cancer Translational Medicine of the Second Affiliated Hospital of Dalian Medical University &amp; Institute of Cancer Stem Cell Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"Sino\u2010US Research Center for Cancer Translational Medicine of the Second Affiliated Hospital of Dalian Medical University &amp; Institute of Cancer Stem Cell Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinrui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Sino\u2010US Research Center for Cancer Translational Medicine of the Second Affiliated Hospital of Dalian Medical University &amp; Institute of Cancer Stem Cell Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology College of Basic Medical Sciences Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baofeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Chromatographic R. &amp; A. 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