SF3B5 is a core component of the 17S U2 SnRNP complex within the spliceosome, functioning as a critical regulator of pre-mRNA splicing 1. It mediates early spliceosome assembly and promotes branch-site adenosine selection, the nucleophile for the first catalytic step of splicing 2. SF3B5 also participates in minor spliceosome function, contributing to U12-type intron splicing 3. Beyond its canonical splicing role, SF3B5 functions as a component of the SAGA transcriptional coactivator complex, where it regulates gene expression independently of splicing machinery 4. Disease relevance is substantial: SF3B5 mutations or dysregulation appear in multiple cancer types. Alternative splicing events involving SF3B5 serve as an independent prognostic indicator in ovarian carcinoma 5, while intravascular NK/T-cell lymphomas display premature termination mutations in SF3B5 alongside aberrant splicing patterns 6. Genome-wide association studies identified SF3B5 as a candidate gene in age-related intestinal amyloidosis 7, and it was implicated as a hub gene in nonalcoholic fatty liver disease pathogenesis 8. The cryo-EM structure of SF3b complexes reveals how splicing modulators like E7107 compete for branch-point adenosine binding, offering therapeutic targets 9. These findings position SF3B5 as both a fundamental splicing component and an emerging biomarker with clinical significance in cancer and metabolic disease.