SF3B3 is a core component of the 17S U2 small nuclear ribonucleoprotein (snRNP) complex, which catalyzes pre-mRNA splicing by promoting branch-site adenosine recognition and early spliceosome assembly. It also participates in minor spliceosome function for U12-type introns. Beyond canonical splicing, SF3B3 regulates alternative splicing of oncogenic transcripts and facilitates DNA repair through interaction with stalled RNA polymerase II. In cancer, SF3B3 is frequently upregulated and drives progression through aberrant splicing of cancer-relevant genes. In colorectal cancer, elevated SF3B3 promotes mTOR exon-skipping and lipogenic signaling, and SF3B3 knockdown synergizes with mTOR inhibitors 1. In hepatocellular carcinoma, SF3B3 acts downstream of MYC to regulate farnesoid X receptor splicing, and combination treatment with an SF3B3 inhibitor and FXR agonist shows synergistic activity 2. In renal cell carcinoma, SF3B3 stimulates EZH2 exon 14 inclusion, promoting a dominant-negative isoform that paradoxically suppresses tumorigenesis, yet elevated SF3B3 correlates with poor survival 3. SF3B3 upregulation also promotes gastric cancer progression via MAPK pathway activation 4. Recently, heterozygous SF3B3 missense variants were identified in a novel spliceosomopathy featuring autism, developmental delay, intellectual disability, and distinctive craniofacial features, with reduced SF3B3 protein levels causing widespread alternative splicing dysregulation and cell-cycle perturbation 5. SF3B3 also restricts Zika virus replication by modulating interferon-stimulated gene expression 6.