UBA2 (ubiquitin-like modifier activating enzyme 2) functions as the catalytic subunit of the heterodimeric SUMO E1-activating enzyme complex, mediating ATP-dependent activation of SUMO proteins and formation of thioester bonds with target substrates 12. The enzyme facilitates SUMOylation of various proteins including PKM2, promoting metabolic reprogramming in cancer cells by enhancing aerobic glycolysis and the Warburg effect 12. UBA2 also SUMOylates NQO1 at lysine residue K240, modulating MAPK pathway signaling in hepatocellular carcinoma progression 3. In laryngeal cancer, UBA2 interacts with TMA7 to regulate autophagy through the PI3K pathway 4. Clinically, UBA2 overexpression correlates with poor prognosis across multiple cancer types including hepatocellular carcinoma, glioma, and multiple myeloma 356. Hyperactive SUMO signaling characterized by high UBA2 expression is associated with proteasome inhibitor resistance in multiple myeloma 6. Additionally, UBA2 mutations cause ACCES syndrome, characterized by aplasia cutis congenita, skeletal abnormalities, and developmental defects 7. Therapeutic targeting of UBA2 with SUMO inhibitors shows promise for cancer treatment, particularly in resistant cases 63.