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Cholangiocarcinoma (CCA), consisting of intrahepatic (IHCCA), perihilar (PHCCA), and distal (DCCA) CCA, is a type of highly aggressive malignancy with a very dismal prognosis. Potential biomarkers and drug targets of CCA are urgently needed. As a new member of the Annexin (ANXA) family, the role of ANXA10 in the progression and prognosis of CCA is unknown. In our study, ANXA10 upregulation was revealed by exome and transcription sequencing in 5 pairs of PHCCA and adjacent tissues. The clinical significance and prognostic value of ANXA10 was evaluated by analyzing its correlation with clinicopathological variables and survival rates. As a result, ANXA10 expression was upregulated in PHCCA and DCCA but not in IHCCA. High ANXA10 expression was significantly associated with poor tumor differentiation and unfavorable prognosis. With in vitro and in vivo experiments, we demonstrated that ANXA10 promoted the epithelial-mesenchymal transition (EMT), proliferation, migration and invasion of the PHCCA cell line QBC939. The key molecule in ANXA10-induced CCA progression was screened by mRNA sequencing. Consequently, PLA2G4A expression was regulated by ANXA10 and it was required in ANXA10-induced metastasis. High PLA2G4A expression also predicted poor prognosis in PHCCA and DCCA. With multiple in vivo experiments, we showed that ANXA10 facilitated EMT and promoted metastasis by upregulating PLA2G4A expression, thus increasing PGE2 levels and activating STAT3. In conclusion, ANXA10 was an independent prognostic biomarker of PHCCA and DCCA but not IHCCA. ANXA10 promoted the proliferation, migration and invasion of PHCCA and facilitated metastasis by promoting the EMT process via the PLA2G4A/PGE2/STAT3 pathway. Our results suggested that ANXA10, PLA2G4A and their downstream molecules, such as COX2 and PGE2, may be promising drug targets of PHCCA and DCCA. Funding Statement: Our study was supported by National Natural Science Foundation of China (Grant no. 81601668), Shandong Province Major Research and Design Program (Grant No. 2018GSF118169), Jinan City Science and Technology Development Program(Grant No. 201805017, 201805013), and Hengrui Hepatobiliary and Pancreatic Foundation (Grant No.Y-2017-144). Declaration of Interests: The authors declare no conflicts of interests. Ethics Approval Statement: All experiments were approved by the Ethics Committee of Qilu Hospital of Shandong University.