The underlying mechanisms include that MANF physically binds to Ser35 of CK19 to inhibit CK19 membrane translocation, MANF facilitates the formation of a complex with CK19 and NICD2, and cytosolic CK19 interacts with AR domain of NICD2 to suppress NICD2 degradation and activate its nuclear signaling, thus accelerating the transformation of mature hepatocytes to ICC cells. The gene discussed is AR; the disease is intrahepatic cholangiocarcinoma.