The Role and Therapeutic Potential of Splicing Factor SF3B6 in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a major global health burden, and effective systemic therapies remain limited. Dysregulated RNA splicing, driven by aberrant activity of core spliceosome components, has emerged as a key hallmark of cancer. SF3B6, a structural subunit of the SF3B complex within the U2 small nuclear ribonucleoprotein (snRNP), is required for branch-point recognition during spliceosome assembly, but its mechanistic role in HCC is poorly understood. Pan-cancer bioinformatic analyses further highlight spliceosome components as recurrently altered, essential for tumor cell survival, and associated with poor prognosis, suggesting that spliceosome subunits may represent shared oncogenic vulnerabilities. Overall design: In this study, I integrated public database analyses with in vitro and in vivo functional assays and transcriptomic profiling to define the role of SF3B6 in HCC. SF3B6 was significantly upregulated in HCC, and higher SF3B6 expression was associated with poor prognosis. SF3B6 depletion suppressed HCC cell proliferation, clonogenic growth, migration, invasion, and tumor formation in vivo. RNA sequencing (RNA-seq) revealed broad transcriptomic remodeling following SF3B6 knockdown, including attenuation of KRAS/RTK–MAPK oncogenic signaling and splicing alterations in KRAS-pathway genes (e.g., PIK3CB and ERBB4). Together, these findings indicate that SF3B6 coordinately regulates oncogenic signaling pathways and alternative splicing programs in HCC and highlight SF3B6 as a potential therapeutic vulnerability in hepatocellular carcinoma.