UBE2K (ubiquitin conjugating enzyme E2 K) is an E2 ubiquitin-conjugating enzyme that catalyzes covalent attachment of ubiquitin to target proteins, primarily generating Lys-48-linked polyubiquitin chains for proteasomal degradation. It functions in the ubiquitin-proteasome system alongside E3 ligases like MARCH5 and BRCA1-BARD1 complex, mediating selective degradation of misfolded proteins and supporting endoplasmic reticulum-associated degradation (ERAD). Mechanistically, UBE2K accepts ubiquitin from E1 complexes and catalyzes its transfer to substrate proteins including huntingtin, GluN2B, c-Myc, and Foxp3. It coordinates with E3 ligases to target specific lysine residues on substrates, controlling protein stability and cellular signaling. In viral infections, UBE2K participates in MHC class I degradation and RB1 protein processing. Clinically, dysregulation of UBE2K associates with multiple pathologies: elevated UBE2K in microglia exacerbates depression through neuroinflammation via the circUBE2K/HNRNPU axis 1; promotes hepatocellular carcinoma progression through c-Myc upregulation 2; mediates synaptic dysfunction in Alzheimer's disease through GluN2B ubiquitination 3; and contributes to acute myeloid leukemia venetoclax resistance when coordinately expressed with MARCH5 4. Conversely, bacterial-derived Amuc_1409 reduces UBE2K-mediated Foxp3 degradation to enhance regulatory T cells and alleviate severe acute pancreatitis 5. These findings identify UBE2K as a key node in protein homeostasis with therapeutic implications across neurodegenerative, malignant, and inflammatory diseases.