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Background: Endometrial cancer (EC) is the fourth most common neoplasm and the eighth leading cause of cancer death in females worldwide. PTPN18 is a member of the protein tyrosine phosphatases (PTP) family, which is associated with the occurrence and progression of various human cancers. PTPN18 was up-regulated in endometrial cancer tissues and high level of PTPN18 promoted proliferation and metastasis of EC cells. Methods: The expression of PTPN18, GPX4 and xCT in endometrial cancer tissues and KLE cells was detected by immunohistochemistry and Western blot, respectively. Lentiviral transfection were used to silence PTPN18 level in KLE cells. The Ros level in KLE cells was examined by ELISA assay. Results: In the present study, we found that silencing of PTPN18 induced ferroptosis in KLE endometrial cancer cells. PTPN18 knockdown increased intracellular ROS level and down-regulated GPX4 and xCT expression. Besides, silencing of PTPN18 also induced the expression of p-p38. Conclusion: We concluded that silencing of PTPN18 might induce ferroptosis by targeting the p-p38/GPX4/xCT axis. The results provide critical insight into the application of PTPN18 knockdown in EC intervention. [ABSTRACT FROM AUTHOR]