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The research aimed to investigate the molecular mechanisms underlying the new application of the antipsychotic drug aripiprazole (APZ) in the treatment of endometrial cancer (EC), as well as its synergistic efficacy when used in combination with progestin. The cell viability assay and proliferation assay demonstrated that APZ exerted a significant inhibitory effect on the proliferation of ISK and KLE cells. Moreover, APZ was found to induce cell apoptosis prominently by flow cytometry. Network pharmacology analysis indicated that the anti\u2010EC effects of APZ were mediated via the epidermal growth factor receptor (EGFR)\/phosphatidylinositol 3\u2010kinase (PI3K)\/protein kinase B (AKT) signaling pathway, which was subsequently confirmed by Western blot analysis. Furthermore, APZ significantly enhanced the proliferation inhibitory effect of medroxyprogesterone acetate (MPA) against progestin\u2010resistant KLE cells, displaying remarkable synergistic activity. These findings position APZ as a promising therapeutic candidate for EC, with potential utility both as a monotherapy and in combination with MPA, offering new avenues for EC treatment strategies.<\/jats:p>","DOI":"10.1002\/ardp.70017","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T04:27:06Z","timestamp":1748233626000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Aripiprazole as an Inhibitor of the EGFR\/PI3K\/AKT Signaling Pathway and Sensitizer of MPA Suppressed Progestin\u2010Resistant Endometrial Cancer Cells"],"prefix":"10.1002","volume":"358","author":[{"given":"Wen","family":"Gan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School 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