Decoding neddylation in malignancies: molecular mechanisms, biological functions, therapeutic resistance, and clinical potential

Neddylation, a protein post-translational modification, regulates diverse molecular biological processes in tumors, governing protein stability, function, subcellular localization, and transcriptional activity. Thus, it plays an essential role in sustaining tumorigenicity and the hallmarks of cancer. In tumors, neddylation is triggered by various forms of cellular stress, involving hypoxia, oxidative stress, and tumor metabolites, all of which drive tumor initiation and progression. This review explores the critical regulatory mechanisms and pathological features of the neddylation cascade in terms of tumor malignant evolution and therapeutic resistance. Additionally, it examines therapeutic strategies targeting NEDD8 modification, offering novel avenues for innovative cancer treatments by disrupting this dynamic, reversible modification process.