SF3B5 is a core component of the 17S U2 snRNP complex, which participates in early spliceosome assembly and mediates recognition of the intron branch site during pre-mRNA splicing by promoting selection of the branch-site adenosine nucleophile. Within the SF3B subcomplex, SF3B5 is required for 'A' complex assembly, enabling stable U2 snRNP binding to the branchpoint sequence. SF3B5 also functions in the minor spliceosome, which splices U12-type introns. Beyond splicing, SF3B5 serves as a subunit of the SAGA transcriptional coactivator complex and is necessary for expression of a subset of SAGA-regulated genes independent of splicing activity. Dysregulation of SF3B5 and related spliceosomal proteins is implicated in multiple malignancies. SF3B5 mutations or copy number losses have been detected in intravascular NK/T-cell lymphoma, where they contribute to complex regulatory abnormalities alongside splicing alterations in oncogenes such as HRAS and VEGFA 1. In ovarian carcinoma, SF3B5 expression correlates with survival-related alternative splicing events and may serve as a prognostic indicator 2. Additionally, SF3B5 was identified as a hub gene in nonalcoholic fatty liver disease, suggesting involvement in metabolic pathology 3. Structurally, SF3B5 is part of the SF3b subcomplex that binds splicing modulators including E7107 and H3B-8800, which compete with branch-point adenosine recognition and represent first-in-class therapeutic opportunities 4. These modulators target spliceosomal mutations that drive cancer-associated splicing dysregulation.