UBE2F is a NEDD8-conjugating E2 enzyme that plays a critical role in protein neddylation, specifically mediating the attachment of NEDD8 to cullin proteins to activate cullin-RING ligases (CRLs) 1. UBE2F primarily neddylates CUL5 in cooperation with E3 ligase RBX2/SAG, thereby activating CRL5 complexes that regulate various cellular processes 23. The enzyme also neddylates other cullins, including its unique requirement for CUL9 neddylation among RBX1-bound cullins 4. UBE2F additionally neddylates non-cullin substrates like RHEB, enhancing mTORC1 signaling by promoting RHEB's lysosomal localization and GTP-binding affinity 5. In immune regulation, UBE2F controls IL-15 receptor signaling in NK cells by facilitating CRL5-mediated receptor degradation 6. UBE2F demonstrates significant disease relevance, being essential for pancreatic cancer cell growth with KRAS mutations and promoting liver tumorigenesis through RHEB neddylation 35. The enzyme represents a promising therapeutic target, with small molecule inhibitors like HA-9104 showing anti-cancer activity by disrupting the UBE2F-CRL5 axis 2. UBE2F expression correlates with patient survival in hepatocellular carcinoma, highlighting its clinical significance 5.