SF3B4 stabilizes SREBF1 via 3'UTR binding to drive hepatocellular carcinoma progression

<h4>Background</h4>Hepatocellular carcinoma (HCC) represents a leading cause of cancer-associated deaths worldwide, and its development is strongly associated with aberrant RNA processing and metabolic reprogramming. Splicing factor 3B subunit 4 (SF3B4), the core component of the U2 spliceosome, has been implicated in tumorigenesis; however, its post-transcriptional functions and role in metabolic regulation in HCC remain unclear.<h4>Methods</h4>SF3B4 expression and its prognostic significance were assessed using TCGA pan-cancer datasets and clinical HCC samples. SF3B4 was either silenced or overexpressed in HCC cell lines, followed by full-length transcriptome sequencing via Oxford Nanopore Technology to analyze global transcriptional and alternative splicing changes. SF3B4-RNA interactions were examined using RNA immunoprecipitation, dual-luciferase reporter assays, RNA pull-down, and mRNA stability assays. Functional assays assessed cell proliferation, apoptosis, invasion, and migration. Rescue experiments involved overexpressing SREBF1 in SF3B4-silenced cells. <i>In vivo</i> tumorigenic effects were validated using xenograft mouse models.<h4>Results</h4>SF3B4 expression was significantly elevated in HCC tissues and correlated with poor OS and DFS. Transcriptomic analyses showed that SF3B4 knockdown induced widespread transcriptional remodeling and extensive alternative splicing reprogramming. Integrative analyses identified sterol regulatory element-binding transcription factor 1 (SREBF1) as a direct downstream target of SF3B4. Mechanistically, SF3B4 bound directly to the 3' untranslated region (3'UTR) of SREBF1 mRNA, enhancing its stability and expression. Functional assays demonstrated that SREBF1 promoted HCC cell proliferation, invasion, and migration, while inhibiting apoptosis. Notably, SREBF1 overexpression partially rescued the malignant phenotypes and transcriptomic alterations induced by SF3B4 knockdown. <i>In vivo</i>, SF3B4 silencing significantly inhibited tumor growth and reduced SREBF1 expression in xenograft models. Clinical validation confirmed the co-upregulation of SF3B4 and SREBF1 in HCC tissues.<h4>Conclusion</h4>This study reveals a novel post-transcriptional mechanism in which SF3B4 promotes HCC progression by stabilizing SREBF1 mRNA through direct 3'UTR binding. The SF3B4-SREBF1 axis connects RNA metabolism dysregulation to lipid metabolic reprogramming, offering new mechanistic insights and potential therapeutic targets for HCC.