OPN directly interacted with β-Catenin and mediated its S675 phosphorylation and nucleus translocation by recruiting and activating MAPK1, which could upregulate Wnt target genes C-MYC, CYCLIN-D1, and PROX1. These results provide a better understanding of the underlying mechanism by which OPN involved in the progression and metastasis of ICC. The gene discussed is PROX1; the disease is intrahepatic cholangiocarcinoma.