UBA3 is the catalytic subunit of the E1 NEDD8-activating enzyme complex (with NAE1/APPBP1), which catalyzes the first committed step in neddylation 1. UBA3 adenylates NEDD8's C-terminal glycine using ATP and transfers the activated NEDD8 to the E2 enzyme UBE2M via a thioester intermediate 12. This post-translational modification regulates cullin-RING ubiquitin ligases, affecting numerous cellular processes including cell cycle progression and protein degradation. Clinically, UBA3 dysregulation is implicated in multiple malignancies. UBA3 is highly expressed in intrahepatic cholangiocarcinoma, where knockdown inhibits proliferation, invasion, and migration through MAPK signaling 3. In lung adenocarcinoma, elevated UBA3 promotes an immunosuppressive microenvironment via NF-κB pathway activation, recruiting immunosuppressive cells and facilitating tumor immune escape 4. UBA3 is also co-dependent with PIK3CA mutations in head and neck squamous cell carcinoma, suggesting neddylation as a therapeutic target 5. Additionally, UBA3 supports interferon-stimulated gene expression in antiviral immunity through interaction with the prefoldin chaperone complex 6. In adult T-cell leukemia, neddylation pathway inhibition via UBA3 suppression increases PD-L1 expression, enhancing immunotherapy efficacy 7. These findings establish UBA3 as a critical hub in cell proliferation, immunity, and cancer pathogenesis.