Hepatic NF-kB-inducing Kinase (NIK) Suppresses Liver Regeneration in Chronic Liver Disease

Summary Hepatocyte replication maintains liver homeostasis and integrity. It is impaired in chronic liver disease, promoting disease progression. Herein, we have identified NF-kB-inducing kinase (NIK) as an unrecognized suppressor of hepatocyte replication. Hepatic NIK was aberrantly activated in chronic liver disease. Hepatocyte-specific deletion of NIK or its downstream mediator IKKα substantially accelerated hepatocyte proliferation and liver regeneration following partial hepatectomy. Mechanistically, NIK and IKKα suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting hepatocyte cell cycle progression. Remarkably, inactivation of hepatic NIK largely reversed suppression of the hepatic JAK2/STAT3 pathway, hepatocyte replication, and liver regeneration induced by either chronic liver injury or metabolic stress. Our data suggest that hepatic NIK acts as a rheostat for liver regeneration to restrain liver overgrowth. Pathologic activation of hepatic NIK blocks hepatocyte replication, likely contributing to liver disease progression.