NEDD8 is a ubiquitin-like protein that functions as a critical post-translational modifier controlling cell cycle progression and protein degradation pathways 1. Primary to NEDD8's function is its conjugation to cullins, where it acts as a structural nexus that activates cullin-RING E3 ligases (CRLs), the largest ubiquitin E3 ligase family 2. NEDD8 attachment to cullins facilitates E2 enzyme recruitment and enables polyubiquitination of regulatory proteins including cyclins, promoting their proteasomal degradation 2. This modification requires sequential enzymatic activation through the E1 complex UBE1C-APPBP1 and E2 enzyme UBE2M 3. Beyond cullin substrates, NEDD8 modifies non-cullin proteins including p53 (which inhibits transcriptional activity) and PTEN (which under high glucose promotes nuclear import and tumor-promoting metabolic effects) 4. Dysregulated neddylation has emerged as clinically significant in multiple diseases. In triple-negative breast cancer, elevated neddylation via the UBC12/TRIM25/TFEB axis promotes chemotherapy resistance to paclitaxel by activating autophagy 5. Conversely, neddylation pathway inhibition using MLN4924 shows therapeutic promise, improving paclitaxel sensitivity and protecting against acetaminophen-induced liver injury by restoring cardiolipin metabolism 6. Recent evidence indicates blocking neddylation accelerates neuronal aging and Alzheimer's disease neurodegeneration 7, suggesting context-dependent therapeutic targeting strategies are essential.