UBE2N (ubiquitin conjugating enzyme E2 N) is a critical E2 ubiquitin-conjugating enzyme that synthesizes non-canonical lysine-63 (K63)-linked polyubiquitin chains, which stabilize proteins rather than targeting them for proteasomal degradation 1. UBE2N functions as a heterodimer with UBE2V1 or UBE2V2 partners and plays essential roles in DNA damage response pathways. It mediates K63-linked polyubiquitination of PCNA during genotoxic stress, facilitating error-free DNA repair and contributing to cell survival after DNA damage 2. In cancer contexts, UBE2N maintains proteostasis by preventing K48-linked ubiquitination and subsequent protein degradation through the immunoproteasome, particularly in acute myeloid leukemia 1. The enzyme also regulates STING signaling through oligomerization-induced ubiquitination, forming a platform for ESCRT recruitment and lysosomal degradation 3. Clinically, UBE2N shows significant disease relevance as elevated expression correlates with Alzheimer's disease pathology and amyloid-β accumulation 4, while its activity promotes chemoresistance and metastasis in lung adenocarcinoma 5. These findings position UBE2N as a promising therapeutic target, with inhibitors showing potential in treating various cancers and neurodegenerative diseases.