RBM25 Drives Hepatocellular Carcinoma Progression by Stabilizing YAP Through Regulating Oncogenic Splicing‐switch of MYPT1

Deregulated alternative splicing (AS) is a hallmark of hepatocellular carcinoma (HCC), yet the specific splicing factors driving oncogenic programs remain largely uncharacterized. Here, we identify RNA-binding 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-derived 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-L isoform. This isoform switch acts as a molecular stabilizer for the transcriptional co-activator YAP, thereby sustaining Hippo pathway dysregulation and tumor growth. Finally, a high-throughput screen of the US drug collection identified candicidin as a small-molecule inhibitor that suppresses RBM25 expression, effectively phenocopying RBM25 knockdown. Our findings define the RBM25-MYPT1-YAP axis as a critical vulnerability in HCC and nominate RBM25 as a viable prognostic biomarker and therapeutic target.