UBE2E1 is an E2 ubiquitin-conjugating enzyme that catalyzes covalent attachment of ubiquitin and ISG15 to target proteins, mediating both monoubiquitination and polyubiquitination 1. The enzyme operates through E3-dependent mechanisms involving complexes like PRC1 and TRIM21, as well as E3-independent pathways 23. Functionally, UBE2E1 catalyzes monoubiquitination of histone H2A at lysine-119 through PRC1 association, regulating gene silencing and cell growth 1. At the primary cilium, UBE2E1 coordinates with MKS1 to regulate β-catenin levels and Wnt signaling 4. Clinically, UBE2E1 emerges as a prognostic biomarker in hepatocellular carcinoma, where elevated expression correlates with increased proliferation, migration, and invasion; high UBE2E1 levels associate with poorer survival outcomes and immune checkpoint inhibitor suitability 56. UBE2E1 dysregulation also features in retinoblastoma progression through ubiquitination pathway alterations 7 and is upregulated in muscle-invasive bladder cancer 8. These findings position UBE2E1 as a potential therapeutic target for cancer intervention.