UBE2L3 encodes a ubiquitin-conjugating enzyme E2 that functions specifically with HECT-type and RBR family E3 ubiquitin ligases, including PRKN/parkin and ARIH1 12. The enzyme accepts ubiquitin from E1 complexes and catalyzes its covalent attachment to target proteins, mediating K11-linked polyubiquitination in vitro 2. UBE2L3 plays critical roles in mitochondrial quality control through the PINK1-PRKN pathway, where it facilitates parkin activation by phosphorylated ubiquitin for mitophagy 13. In disease contexts, UBE2L3 exhibits tumor-suppressive properties in several cancers. In gastric cancer, UBE2L3 upregulation correlates with poor prognosis and enhanced proliferation/invasion 4. However, UBE2L3 degradation by the HPV-induced ligase MARCHF8 stabilizes the viral E7 oncoprotein, promoting head and neck cancer development 5. UBE2L3 also functions as a protective factor in psoriasis by suppressing IL-1β secretion through TRIM21 degradation and inhibiting CXCL16/CXCR6-mediated inflammatory signaling in keratinocytes 67. Additionally, UBE2L3 mediates non-canonical sugar-mediated ubiquitination that impairs Nrf1 transcription factor activation 2. These diverse functions highlight UBE2L3's importance in cellular homeostasis, inflammation, and cancer pathogenesis.