UBE2O is a unique E2/E3 hybrid ubiquitin-conjugating enzyme that displays dual enzymatic activities and functions as a critical regulator of protein ubiquitination 1. The enzyme mediates monoubiquitination of diverse substrates including RECQL4, BAP1, PTRF/CAVIN1, and L3MBTL2, targeting them for proteasomal degradation or altering their subcellular localization 2345. UBE2O also regulates signal transduction through substrate-specific mechanisms, such as negatively regulating interferon signaling by degrading IFIT3 and promoting tumor growth 6. In disease pathogenesis, elevated UBE2O expression is associated with multiple malignancies 17. UBE2O promotes hepatocellular carcinoma progression and radiotherapy resistance by suppressing DNA damage responses and homologous recombination-mediated DSB repair through RECQL4 degradation 82. In osteosarcoma, UBE2O-mediated degradation of the tumor suppressor L3MBTL2 drives oncogenic condensate dissolution 5. Conversely, pharmacological inhibition of UBE2O by arsenic trioxide enhances therapeutic responses 56, positioning UBE2O as a promising therapeutic target for cancer treatment and overcoming drug/radiation resistance.