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Current diagnostic and therapeutic strategies have notable limitations, including delayed diagnosis and adverse effects. The transcription factor forkhead box A2 (FOXA2), which is exclusively expressed in the uterine glandular epithelium, regulates key genes involved in endometrial proliferation, differentiation, fertility, and hormone response. While FOXA2 expression is reduced in the endometrial tissue of women with endometriosis, its pathophysiological role in the disease is not well understood. In this study, we report that endometriosis significantly reduced FOXA2 expression in the eutopic endometrium of mice with endometriosis compared to sham controls, accompanied by decreased expression of its downstream gene, CXCL15. To evaluate the effect of FOXA2 loss in endometriosis, we surgically induced endometriosis by transplanting control\n                    <jats:italic>Rosa26<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>mTmG\/+<\/jats:italic>\n                    <\/jats:sup>\n                    or\n                    <jats:italic>Pgr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>cre\/+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>Foxa2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>f\/f<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>Rosa26<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>mTmG\/+<\/jats:italic>\n                    <\/jats:sup>\n                    (\n                    <jats:italic>Foxa2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>d\/d<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>Rosa26<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>mTmG\/+<\/jats:italic>\n                    <\/jats:sup>\n                    ) endometrial tissue into the peritoneal cavity of mice. The number and weight of ectopic lesions were significantly increased in the mice with\n                    <jats:italic>Foxa2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>d\/d<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>Rosa26<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>mTmG\/+<\/jats:italic>\n                    <\/jats:sup>\n                    ectopic lesions compared to controls. Furthermore, progesterone receptor expression was significantly reduced in the endometrial epithelium from mice with\n                    <jats:italic>Foxa2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>d\/d<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>Rosa26<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>mTmG\/+<\/jats:italic>\n                    <\/jats:sup>\n                    ectopic lesions compared to mice with control ectopic lesions. Importantly, treatment with leukemia inhibitory factor (LIF), a cytokine regulated by FOXA2, significantly reduced ectopic lesion formation in\n                    <jats:italic>Foxa2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>d\/d<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>Rosa26<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>mTmG\/+<\/jats:italic>\n                    <\/jats:sup>\n                    endometriosis mice compared to vehicle\u2010treated mice. This study demonstrates that FOXA2 loss results in an increase in endometriosis incidence and that treatment with LIF offers a novel promising therapeutic approach for endometriosis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202403182r","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T12:01:44Z","timestamp":1741694504000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>FOXA2<\/scp>\n                    loss results in an increase of endometriosis development and\n                    <scp>LIF<\/scp>\n                    reveals a therapeutic effect for endometriosis"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4583-8731","authenticated-orcid":false,"given":"Md Saidur","family":"Rahman","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women's Health University of Missouri School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7823-5457","authenticated-orcid":false,"given":"Tae Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women's Health University of Missouri School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9107-152X","authenticated-orcid":false,"given":"Breton F.","family":"Barrier","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women's Health University of Missouri School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2815-766X","authenticated-orcid":false,"given":"Thomas E.","family":"Spencer","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women's Health University of Missouri School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1484-4998","authenticated-orcid":false,"given":"Andrew M.","family":"Kelleher","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women's Health University of Missouri School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5368-6478","authenticated-orcid":false,"given":"Jae\u2010Wook","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women's Health University of Missouri School of Medicine  Columbia Missouri 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