Neddylation and MASLD: From Pathophysiology to Therapy

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is intimately linked to the dysregulation of key transcription factors or enzymes involved in hepatic metabolism. Neddylation, a post-translational modification, refers to the covalent attachment of neuronal precursor cell-expressed developmentally down-regulated 8 (Nedd8) to specific substrates and plays a significant role in regulating protein conformation, localisation and activity. The connection between neddylation and MASLD is a burgeoning area of research that is presently the focus of extensive study. In this review, we focus on the latest advancements regarding the role of neddylation in various critical pathological stages of MASLD. We summarise both the confirmed and potential evidence of neddylation's involvement in the onset and progression of MASLD. Additionally, we review the biological basis of neddylation, its correlation with the progression of MASLD and propose potential directions for basic and translational research in this field. Finally, we emphasise the potential therapeutic applications of targeting neddylation in MASLD, particularly in designing pharmacological inhibitors that have broad effects on MASLD.