The role of neddylation in colorectal cancer and its therapeutic potential.

Colorectal cancer (CRC) is the third most common malignancy worldwide, and the five-year survival rate for patients with metastatic disease remains below 15% despite advances in current therapeutic approaches. Post-translational modifications (PTMs) play a pivotal role in CRC initiation and progression, among which neddylation—a critical ubiquitin-like modification—is closely associated with tumor cell proliferation, migration, and chemotherapy resistance. This modification covalently attaches neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) to lysine residues of substrate proteins, thereby regulating protein stability, DNA repair, and immune responses. In CRC, key enzymes in the neddylation pathway, such as NAE1, UBE2M, and DCUN1D1, are frequently aberrantly activated, leading to the stabilization of key oncoproteins and cell-cycle regulators by preventing their ubiquitin-mediated degradation, thereby promoting tumor progression and drug resistance. Although neddylation has been extensively studied in various cancer types, its precise role in CRC has not been fully elucidated. Recent studies have shown that targeting neddylation—particularly with NAE1 inhibitors such as MLN4924—can significantly suppress tumor progression and offer new therapeutic opportunities to overcome chemoresistance. This review systematically summarizes the roles of neddylation in CRC pathogenesis, chemoresistance, and immune microenvironment remodeling, with a focus on the clinical potential of combining neddylation-targeted inhibitors with chemotherapy and immunotherapy, as well as the prospective application of liquid biopsy in precision monitoring, aiming to provide a theoretical basis and future directions for molecular targeted therapy and clinical translation in CRC.