{"paper_id":"752c057c-c555-475a-a30d-6675e5bdd593","body_text":"Abstract\nThis study evaluates the synergistic therapeutic effect of metformin (MET) combined with medroxyprogesterone acetate (MPA) on endometriosis (EM) and investigates the involvement of the steroid receptor coactivator-1 (SRC-1) and mitogen-inducible gene 6 (MIG-6). Immunohistochemical analysis revealed significantly decreased SRC-1, progesterone receptor (PGR), and MIG-6 protein expression in human ectopic EM lesions compared to normal eutopic endometrium. In an EM mouse model, the combination of metformin (MET) and MPA resulted in the greatest reduction of ectopic lesion size and weight compared to either treatment alone. This combination therapy also uniquely increased serum Eotaxin and decreased interleukin-12p40 levels. Transcriptome analysis demonstrated specific enrichment of immune activation pathways only in the combination treatment group. In vitro, using the human endometriosis epithelial cell line 12Z, the MET and MPA combination significantly suppressed cell proliferation and migration, concomitant with an upregulation of SRC-1, PGR, and MIG-6 messenger RNA expression. We conclude that MET enhances the therapeutic efficacy of MPA against EM. This effect may be mediated through MIG-6 signaling and involves the upregulation of SRC-1, inhibiting ectopic cell proliferation and migration, and inhibiting endometriotic lesion progression, representing a novel strategy to overcome progesterone resistance.\nKey messages\n-\nSRC-1, MIG-6, and PGR are downregulated in human endometriotic lesions.\n-\nMET and MPA act cooperatively to suppress lesion growth in a murine model.\n-\nCombination therapy increases Eotaxin levels while decreasing IL-12p40 in mice.\n-\nMET and MPA activate immune surveillance pathways within lesions.\n-\nMET and MPA synergistically inhibit endometriotic cell growth and migration.\nSimilar content being viewed by others\nData availability\nThe raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2025) in National Genomics Data Center (Nucleic Acids Res 2025), China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA: CRA034922) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa.\nReferences\nAs-Sanie S, Mackenzie SC, Morrison L, Schrepf A, Zondervan KT, Horne AW, Missmer SA (2025) Endometriosis: a review. 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J Steroid Biochem 26:313–319. https://doi.org/10.1016/0022-4731(87)90095-1\nAcknowledgements\nThank the resources from Biorender (https://app.biorender.com) for helping us construct Fig. 5.\nFunding\nThis work was supported by the Shenzhen Science and Technology Program (No. JCYJ20220531094012027), Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases (SYSPG20241211173501001), the Shenzhen Key Medical Discipline Construction Fund (No. SZXK027), the Shenzhen Science and Technology Program (JCYJ20220818102811025), the Shenzhen High-level Hospital Construction Fund and Peking University Shenzhen Hospital Scientific Research Fund (KYQD2024433), the Scientific Research Foundation of Peking University Shenzhen Hospital (KYQD2023289), the Beijing Science and Technology Innovation Medical Development Foundation (KC2023-JX-0186-RZ105) and the Shenzhen Science and Technology Program (No. RCBS20231211090710015).\nAuthor information\nAuthors and Affiliations\nContributions\nGuanwen Gao: writing—original draft, writing—review and editing, methodology, formal analysis; Lvfang Duan: resources, investigation, methodology; Fanfan Zhu: resources, validation; Wenkui Dai: software, formal analysis; Lina Geng: resources; Degao Liu: resources; Jinju Lin: resources; Huashan Zhao: supervision, project administration, writing—review and editing; Yunfei Wang: project administration, writing—review and editing; Changzhong Li: visualization, validation, methodology, funding acquisition, data curation, supervision, writing—review and editing; all authors read and approved the final manuscript.\nCorresponding author\nEthics declarations\nEthics approval\nThe study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committees of Peking University Shenzhen Hospital (number: 2023–094). 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Metformin sensitizes endometriosis to medroxyprogesterone acetate treatment through MIG-6 mediated signaling. J Mol Med 104, 49 (2026). https://doi.org/10.1007/s00109-026-02655-z\nReceived:\nRevised:\nAccepted:\nPublished:\nVersion of record:\nDOI: https://doi.org/10.1007/s00109-026-02655-z","source_license":"public-domain-us","license_restricted":false}