Biliary <scp>NF</scp> ‐ <scp>κB</scp> ‐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.