UBA1 encodes ubiquitin-like modifier activating enzyme 1, the primary E1 enzyme that catalyzes the first step of ubiquitin conjugation in the ubiquitin-proteasome system 1. UBA1 activates ubiquitin by adenylating its C-terminal glycine residue with ATP and linking it to a cysteine residue in E1, forming a ubiquitin-E1 thioester intermediate 1. Beyond protein degradation, UBA1 is essential for DNA damage response, promoting recruitment of TP53BP1 and BRCA1 at damage sites and facilitating formation of radiation-induced foci 1. Clinically, UBA1 mutations cause VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic), an adult-onset autoinflammatory disorder predominantly affecting men over 50 2. Somatic mutations clustered at methionine-41 eliminate the canonical UBA1b cytoplasmic isoform, impairing ubiquitination and activating innate immune pathways 12. This results in systemic inflammation manifesting as fever, chondritis, vasculitis, and neutrophilic skin/pulmonary involvement, frequently accompanied by myelodysplastic syndrome and macrocytic anemia with characteristic vacuoles in myeloid precursors 12. Treatment options include glucocorticoids, JAK inhibitors, tocilizumab, azacitidine, and hematopoietic stem cell transplantation as the only curative approach 23.