CircPCNXL2, a circular RNA, was identified as upregulated in intrahepatic cholangiocarcinoma (ICC) tissues and cell lines. The study aimed to investigate the biological functions and mechanisms of CircPCNXL2 in ICC. CircPCNXL2 was found to promote proliferation and metastasis of ICC both in vitro and in vivo. Mechanistically, CircPCNXL2 interacted with STRAP, enhancing the interaction between STRAP and MEK1/2, thereby activating the ERK/MAPK signaling pathway. Additionally, CircPCNXL2 regulated the expression of SRSF1 by sponge miR-766-3p, further activating the ERK/MAPK pathway. Finally, CircPCNXL2 partially inhibited the anti-tumor activity of trametinib, a MEK1/2 inhibitor, in vivo. These findings suggest that CircPCNXL2 plays a crucial role in ICC progression and may serve as a promising biomarker and therapeutic target.CircPCNXL2, a circular RNA, was identified as upregulated in intrahepatic cholangiocarcinoma (ICC) tissues and cell lines. The study aimed to investigate the biological functions and mechanisms of CircPCNXL2 in ICC. CircPCNXL2 was found to promote proliferation and metastasis of ICC both in vitro and in vivo. Mechanistically, CircPCNXL2 interacted with STRAP, enhancing the interaction between STRAP and MEK1/2, thereby activating the ERK/MAPK signaling pathway. Additionally, CircPCNXL2 regulated the expression of SRSF1 by sponge miR-766-3p, further activating the ERK/MAPK pathway. Finally, CircPCNXL2 partially inhibited the anti-tumor activity of trametinib, a MEK1/2 inhibitor, in vivo. These findings suggest that CircPCNXL2 plays a crucial role in ICC progression and may serve as a promising biomarker and therapeutic target.