UBE2G1 (ubiquitin conjugating enzyme E2 G1) is an E2 ubiquitin-conjugating enzyme that accepts ubiquitin from E1 complexes and catalyzes covalent attachment to target proteins through K48- and K63-linked polyubiquitination 1. UBE2G1 functions as a key component of multiple E3 ubiquitin ligase complexes, including the CRL4CRBN complex involved in cereblon-mediated protein degradation. Mechanistically, UBE2G1 cooperates with E3 ligases like TRAF7 to promote K48-linked polyubiquitination of substrates, targeting them for proteasomal degradation 2. The enzyme contains a distinctive acidic loop with tyrosine residues that enhance ubiquitin binding and catalytic activity 1. UBE2G1 demonstrates broad disease relevance. It mediates degradation of neomorphic substrates of the cereblon complex when engaged by immunomodulatory drugs (lenalidomide, pomalidomide), making it essential for therapeutic efficacy against multiple myeloma 3. UBE2G1 has been implicated in Alzheimer's disease pathology, with increased plasma peptide frequency in AD patients 4. Additionally, UBE2G1 participates in gestational diabetes mellitus through the circ-PNPT1/miR-144-3p/UBE2G1 regulatory axis affecting endothelial dysfunction 5, and in osteoarthritis progression via the circRNA-UBE2G1/miR-373/HIF-1α pathway 6. Clinically, UBE2G1 activity loss confers resistance to cereblon-targeting drugs but cells remain sensitive to more potent degraders 3, highlighting its importance in therapeutic response and potential as a drug resistance marker.