Hepatic Neddylation Deficiency Triggers Fatal Liver Injury via Inducing NF‐κB‐inducing Kinase and Oxidative Stress

The conjugation of NEDD8 to target proteins, termed neddylation is aberrant in many pathological diseases. Its relevance to liver function and failure remains poorly understood. Here, we first identified dysregulated expression of neddylation enzymes ( e.g. NAE1, a regulatory subunit of the only NEDD8 E1 enzyme) in human HBV‐induced acute liver failure (ALF). Embryonic–onset deletion of NAE1 in hepatocytes led to severe hepatomegaly, formation of numerous cysts, inflammation, and fibrosis, which ultimately resulted in ALF in mice. Adult–onset hepatic deletion of NAE1 caused ALF with 100% mortality within 30 days post deletion. Mechanistically, hepatic neddylation deficiency triggers glutathione deficiency, oxidative stress, mitochondrial dysfunction, and reprogramming of mature hepatocytes to fetal‐like cells, potentiating liver injury. Importantly, we identified NF‐κB‐inducing kinase (NIK), a stress kinase aberrantly activated in chronic and acute liver diseases, is a novel neddylation substrate. Neddylation of NIK promotes its ubiquitination and degradation; and inhibition of neddylation caused NIK overactivation, accentuating hepatocyte damage. Notably, oral N‐acetylcysteine (NAC) administration attenuated lethal liver injury caused by hepatic NAE1 deletion, with improved liver function and mortality. Therefore, hepatic neddylation is essential in maintaining postnatal and adult liver homeostasis, and the novel neddylation targets/pathways may endow us with new insights into therapeutically intervening ALF progression.