{"paper_id":"407203c8-176f-4078-b6cf-7aae4fdd720e","body_text":"Abstract\nEndometriosis is a common gynecological disease that causes severe pain and infertility. However, the available treatments for EMS are limited. SCM-198, a synthetic form of leonurine, possesses various abilities, including anti-inflammatory, immunomodulatory, antioxidant, anti-fibrotic, and anti-proliferative effects. Previous studies have shown that SCM-198 can inhibit the growth of ectopic lesions, but the specific mechanism remains unknown. The results of our studies indicate that SCM-198 significantly suppresses the endometriotic growth of EMS mice. Enrichment analysis of RNA-seq indicates that SCM-198 is involved in T cell differentiation, activation, cytokine production, stimulation of chemotaxis, and migration. Flow cytometry reveals that SCM-198 reverses the decreased proportions of IFN-γ + T cells and CCR5 + T cells in ectopic lesions. RNA-seq analysis shows that SCM-198 enhances the expression of CCL5 in the ectopic lesions, and western blot is conducted to verify this conclusion both in vivo and in vitro. These findings demonstrate that SCM-198 reverses the decreased proportions of IFN-γ + T cells and CCR5 + T cells, alleviating the growth of mouse ectopic lesions, and the changes in CCR5 + T cells are likely due to the reduced expression of CCL5.\nSimilar content being viewed by others\nReferences\nTaylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397(10276):839–52.\nChapron C, et al. Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol. 2019;15(11):666–82.\nVercellini P, et al. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–75.\nFranca PRC, Lontra ACP, Fernandes PD. Endometriosis: a disease with few direct treatment options. Molecules, 2022. 27(13).\nFalcone T, Flyckt R. Clinical management of endometriosis. Obstet Gynecol. 2018;131(3):557–71.\nCapezzuoli T, et al. Hormonal drugs for the treatment of endometriosis. Curr Opin Pharmacol. 2022;67:102311.\nSymons LK, et al. The immunopathophysiology of endometriosis. Trends Mol Med. 2018;24(9):748–62.\nChen S, et al. Peritoneal immune microenvironment of endometriosis: role and therapeutic perspectives. Front Immunol. 2023;14:1134663.\nKisovar A, et al. The role of CD8 + T cells in endometriosis: a systematic review. Front Immunol. 2023;14:1225639.\nWitz CA, et al. Characterization of lymphocyte subpopulations and T cell activation in endometriosis. Am J Reprod Immunol. 1994;32(3):173–9.\nXiao F, Liu X, Guo SW. Interleukin-33 derived from endometriotic lesions promotes fibrogenesis through inducing the production of profibrotic cytokines by regulatory T cells. Biomedicines, 2022. 10(11).\nZhu T, et al. Identifying immune cell infiltration and hub genes related to M2 macrophages in endometriosis by Bioinformatics Analysis. Reprod Sci. 2023;30(11):3388–99.\nVallve-Juanico J, Houshdaran S, Giudice LC. The endometrial immune environment of women with endometriosis. Hum Reprod Update. 2019;25(5):564–91.\nMiao LL, et al. Leonurus japonicus (Chinese motherwort), an excellent traditional medicine for obstetrical and gynecological diseases: a comprehensive overview. Biomed Pharmacother. 2019;117:109060.\nJin M, et al. Leonurine suppresses neuroinflammation through promoting oligodendrocyte maturation. J Cell Mol Med. 2019;23(2):1470–85.\nLi YY, et al. SCM-198 alleviates endometriosis by suppressing Estrogen-ERalpha mediated differentiation and function of CD4(+)CD25(+) Regulatory T cells. Int J Biol Sci. 2022;18(5):1961–73.\nLin YK, et al. SCM-198 prevents endometriosis by reversing low autophagy of endometrial stromal cell via balancing ERalpha and PR signals. Front Endocrinol (Lausanne). 2022;13:858176.\nShanmugasundaram U, et al. Phenotype and functionality of CD4 + and CD8 + T cells in the upper reproductive tract of healthy premenopausal women. Am J Reprod Immunol. 2014;71(2):95–108.\nUekusa Y, et al. A pivotal role for CC chemokine receptor 5 in T-cell migration to tumor sites induced by interleukin 12 treatment in tumor-bearing mice. Cancer Res. 2002;62(13):3751–8.\nGough M, et al. Gene therapy to manipulate effector T cell trafficking to tumors for immunotherapy. J Immunol. 2005;174(9):5766–73.\nBulun SE, et al. Endometriosis. Endocr Rev. 2019;40(4):1048–79.\nLi YY, et al. Leonurine: from gynecologic medicine to pleiotropic agent. Chin J Integr Med. 2020;26(2):152–60.\nNie J, Liu X. Leonurine attenuates hyperalgesia in mice with induced adenomyosis. Med Sci Monit. 2017;23:1701–6.\nPashizeh F, et al. Alterations of CD4 + T cell subsets in blood and peritoneal fluid in different stages of endometriosis. Int J Fertil Steril. 2020;14(3):201–8.\nJerman LF, et al. The lymphatic system in endometriosis: a pilot study of endometrial-like cells and immune cell populations in lymph nodes associated with deep infiltrating bowel lesions. Reprod Sci. 2020;27(4):977–87.\nPodgaec S et al. Th1 and Th2 ummune responses related to pelvic endometriosis. Rev Assoc Med Bras. 2010;56(1):92– 8.\nBorthwick LA, Wynn TA, Fisher AJ. Cytokine mediated tissue fibrosis. Biochim Biophys Acta. 2013;1832(7):1049–60.\nGogacz M, et al. Increased percentage of Th17 cells in peritoneal fluid is associated with severity of endometriosis. J Reprod Immunol. 2016;117:39–44.\nAhn SH, et al. IL-17A contributes to the pathogenesis of endometriosis by triggering proinflammatory cytokines and angiogenic growth factors. J Immunol. 2015;195(6):2591–600.\nOlkowska-Truchanowicz J, et al. CD4(+) CD25(+) FOXP3(+) regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis. Hum Reprod. 2013;28(1):119–24.\nTanaka Y, et al. Exacerbation of endometriosis due to regulatory T-cell dysfunction. J Clin Endocrinol Metab. 2017;102(9):3206–17.\nOlkowska-Truchanowicz J et al. Endometriotic peritoneal fluid stimulates recruitment of CD4(+)CD25(high)FOXP3(+) Treg cells. J Clin Med, 2021. 10(17).\nTan A, et al. A potential antiviral role for CCR5 + CD8 + T cells in children with hepatitis B. J Med Virol. 2024;96(5):e29661.\nGonzalez-Martin A, et al. Maximal T cell-mediated antitumor responses rely upon CCR5 expression in both CD4(+) and CD8(+) T cells. Cancer Res. 2011;71(16):5455–66.\nFunding\nThis work was supported by grants from the National Key R&D Program of China (2021YFE0206500 to M.D.), National Natural Science Foundation of China (82271713, 81630036, and 31970859 to M.D.), and the Research Program of Shanghai 4th People’s Hospital (sykyqd09001).\nAuthor information\nAuthors and Affiliations\nCorresponding authors\nEthics declarations\nEthical Approval\nOur study was approved by the Research Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University, and all experiments were performed per the relevant guidelines and regulations (No. Kyy2023-41) (Shanghai, China).\nConflict of Interest\nThe authors declare that they have no conflict of interest.\nAdditional information\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nRights and permissions\nSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.\nAbout this article\nCite this article\nLu, Y., Li, Y., Li, Y. et al. SCM-198 Inhibits EMS Development by Reversing Decreased Proportions of IFN-γ+T Cells and CCR5+T Cells. Reprod. Sci. 32, 2180–2189 (2025). https://doi.org/10.1007/s43032-025-01823-9\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s43032-025-01823-9","source_license":"CC0","license_restricted":false}