NAE1 (NEDD8 activating enzyme E1 subunit 1) is the regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme complex that catalyzes protein neddylation, a critical post-translational modification 1. NAE1 activates NEDD8 through adenylation and thioester bond formation, subsequently transferring NEDD8 to E2 enzymes like UBE2M for conjugation to target proteins [UniProt data]. This modification regulates cell cycle progression, cell growth, and apoptosis [UniProt data]. NAE1 has emerged as a significant therapeutic target across multiple diseases. In cardiac hypertrophy, K238 crotonylation of NAE1 promotes gelsolin neddylation, enhancing cytoskeletal remodeling and pathological hypertrophy progression 1. Genome-wide association studies identify NAE1 as a putatively causal gene and potential intervention target for heart failure prevention 2. In cholangiocarcinoma, NAE1-mediated hyper-neddylation promotes tumor cell proliferation and survival; pevonedistat (NAE1 inhibitor) halts tumorigenesis in multiple in vivo models 3. NAE1 inhibition also prevents acetaminophen-induced liver injury by modulating cardiolipin metabolism 4 and attenuates lupus progression by promoting double-negative T cell apoptosis through Bim stabilization 5. In immunotherapy contexts, NAE1-mediated neddylation serves as a proteomic checkpoint for CD8+ T cell activation and antitumor function 6, while NAE1 expression predicts clinical outcomes and immune infiltration in hepatocellular carcinoma 7.