Abstract: The neddylation of proteins, which involves tagging substrate proteins with neural precursor cell-expressed developmentally down-regulated protein 8 (NEDD8), is one of the most important post-translational modifications. It has been shown to play significant roles in various biological processes such as cell growth, apoptosis, and signal transduction. Recent research has found a close association between protein neddylation and the occurrence and development of inflammatory diseases. This article begins by reviewing the neddylation cascade, including its biochemical processes and regulation, and further expounds on its effects by regulating key proteins in inflammatory signaling pathways, discovering that it acts as a crucial regulator for the characteristics and functions of innate immune cells (neutrophils, macrophages, and dendritic cells) as well as adaptive immune cells. Subsequently, we focus on reviewing the roles and mechanisms of protein neddylation in various inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, liver fibrosis, pancreatitis, atherosclerosis, and acute lung injury. The potential of protein neddylation as a therapeutic target is discussed. Finally, we discussed the significance and potential clinical values of current small-molecule neddylation inhibitors (particularly MLN4924 and TAS4464) as an promising therapeutic approach in the treatment of inflammation, further, we proposed possible future research directions and key issues to be addressed. 

Key words: neddylation, neural precursor cell expressed developmentally downregulated protein 8, MLN4924, immune cells, inflammatory signaling pathway, deneddylation