USP39 (ubiquitin specific peptidase 39) is a deubiquitinating enzyme that functions as both a component of the U4/U6-U5 tri-snRNP spliceosome complex and a regulator of protein stability through deubiquitination 1. As a spliceosome component, USP39 is essential for pre-mRNA splicing and regulates alternative splicing of numerous genes, including autophagy-related genes like HSF1 in hepatocytes and CTLA-4 in regulatory T cells 23. USP39 deficiency leads to impaired spliceosome assembly and pathogenic cryptic splicing that produces misfolded proteins, causing proteotoxic aggregates and cell death 1. Through its deubiquitinating activity, USP39 stabilizes key proteins including β-catenin by direct deubiquitination and ZEB1 in multiple myeloma cells 45. USP39 also enhances NAT10 protein stability through protein-protein interactions, promoting cancer metastasis 6. Clinically, USP39 is overexpressed in various cancers including hepatocellular carcinoma, multiple myeloma, and leukemia, where high expression correlates with poor patient survival 758. USP39's dual role in RNA splicing regulation and protein stabilization makes it a critical regulator of cellular homeostasis and a potential therapeutic target in cancer.