Biliary NF ‐ κB ‐Inducing Kinase Promotes Ductular Reaction, Inflammation, and Fibrosis and Impedes Liver Disease Resolution

NF‐κB‐inducing kinase (NIK) is selectively upregulated in cholangiocytes during chronic liver disease, but its role in disease progression is poorly understood. We here show that cholangiocyte‐specific overexpression of NIK ( NIK Tg ) exacerbates liver disease progression. NIK Tg mice were generated using a CK19‐CreERT/loxp system. NIK Tg and wild‐type control ( NIK Con ) mice were treated with thioacetamide (TAA) or 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) to induce liver disease. In a separate cohort, mice were allowed a 2‐week recovery period following 4 weeks of TAA administration. NIK was also ablated in human HuCC‐T1 cholangiocyte cultures (HuCC‐T1 NIK−/− ), and either wild‐type NIK or the NIK G885R mutant (defective in activating IKKα) was reintroduced into HuCC‐T1 NIK−/− cells. We found that NIK Tg mice exhibited a markedly elevated liver pathology—pronounced cholangiocyte expansion, liver inflammation, and fibrosis—upon exposure to DDC or TAA, leading to death. NIK Tg mice, unlike NIK Con controls, failed to recover after cessation of toxin exposure. Deletion of NIK in HuCC‐T1 NIK−/− cells reduced cell proliferation and survival and blunted secretion of cholangiokines that activate macrophages and hepatic stellate cells (HSCs). Re‐introduction of NIK into HuCC‐T1 NIK−/− cells fully rescued these defects. In contrast, re‐introduction of NIK G885R partially rescued the defects. Collectively, these findings indicate that biliary NIK drives ductular reaction and pathogenic cholangiokine secretion through both IKKα‐dependent and ‐independent mechanisms. Furthermore, aberrant biliary NIK impedes liver injury resolution and fibrosis regression, thereby contributing to poor outcomes.