UBA5 is an E1-like enzyme that catalyzes the first step of ufmylation, a ubiquitin-like protein modification system 1. It activates UFM1 by adenylating its C-terminal glycine with ATP and forming a thioester bond with a cysteine residue in the UBA5 homodimer, subsequently transferring UFM1 to the E2-like enzyme UFC1 via a trans-binding mechanism 2. Ufmylation regulates diverse cellular processes including endoplasmic reticulum (ER) homeostasis, autophagy initiation, and response to proteotoxic stress 3. Pathogenic UBA5 variants cause developmental and epileptic encephalopathy 44, characterized by developmental delays, epilepsy, and intellectual disability with defects in GABAergic interneuron development and perturbation of ER homeostasis 1. UBA5 dysfunction also impairs autophagy through reduced BECN1 stabilization and compromised assembly of the phosphatidylinositol-3-kinase complex 3. Beyond neurological disease, UBA5 expression is elevated in lung adenocarcinoma and breast cancer, where it promotes tumor growth, M2 macrophage polarization, cisplatin resistance, and HIF1α stabilization under hypoxic conditions 45. UBA5 inhibition emerges as a therapeutic strategy for both neurological disorders and cancer, enhancing anti-PD-1 immunotherapy response in hypoxic tumors 5.