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Our KO screen in patient-derived HCC organoid showed splicing factor 3b subunit 4 (SF3B4) to be top-ranked, conferring prosurvival signal in HCC organoid and driving tumorigenic potentials in both hepatic progenitor organoids and hydrodynamic tail vein injection HCC murine model. The combined RNA immunoprecipitation sequencing, long-read isoform sequencing, and transcriptome revealed characteristic splicing landscape regulated by SF3B4 and identified T-box transcription factor 3 (TBX3) variant TBX3+2a as a potent downstream effector. Our findings highlighted vital roles of SF3B4 in HCC cell survival and tumor progression, and the phenomenon of ferroptosis resistance in patients unresponsive to first-line agent lenvatinib.<\/jats:p>","DOI":"10.1126\/sciadv.adw7181","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:59:09Z","timestamp":1760119149000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":13,"title":["Genome-wide CRISPR screen identifies splicing factor SF3B4 in driving hepatocellular carcinoma"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6335-8654","authenticated-orcid":true,"given":"Yue","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Surgery, Sir Y.K. 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