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Our previous work identified ferroptosis-related dipeptidyl Peptidase 4 (DPP4) as a key regulator of endometrial receptivity in PCOS, though its mechanism remained unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We aimed to explore the regulatory mechanism of DPP4 in the occurrence and tolerance of endometrial ferroptosis in PCOS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using high dose (HD) DHEA-induced rats and hormone-treated (E2 and HD DHEA) telomerase-immortalized human endometrial stromal cells (T-HESCs), we investigated DPP4\u2019s role in endometrial ferroptosis and receptivity. We evaluated the correlation of specific endometrial marker expression levels with reproductive outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Phenotypic assessments revealed elevated endometrial Fe\n                      <jats:sup>2+<\/jats:sup>\n                      accumulation, antioxidant dysfunction, mitochondrial damage, and enhanced estrogen\/androgen receptor expression in PCOS models. DPP4 inhibition via sitagliptin improved decidualization responses and receptivity markers in rats prior to pregnancy. In T-HESCs, downregulated DPP4 could suppress hormone receptor expression and ferroptosis markers. Functional validation using BeWo spheroid implantation assays demonstrated restored endometrial receptivity following DPP4 intervention. Mechanistically, DPP4-driven ferroptosis exacerbated PCOS-associated endometrial dysfunction, while its suppression would enhance stromal cell decidualization capacity and implantation potential. Consistent with these findings, evaluation of endometrial specimens from PCOS patients confirmed a marked reversal of ferroptosis-related markers following sitagliptin intervention, which was further associated with significantly improved reproductive outcomes, including higher clinical pregnancy and live birth rates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Reducing DPP4 expression not only inhibited ferroptosis but also improved the PCOS phenotype of the endometrium, ultimately influencing changes in endometrial receptivity, and indicating the ferroptosis-related protein DPP4 as a promising therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-025-00786-5","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:22:17Z","timestamp":1766499737000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The mechanism study of targeting DPP4 in regulating ferroptosis and its influence on endometrial receptivity in PCOS"],"prefix":"10.1186","volume":"16","author":[{"given":"Jian","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajun","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengbin","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiliang","family":"Jian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"786_CR1","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1016\/S0015-0282(16)53524-9","volume":"53","author":"RJ Paulson","year":"1990","unstructured":"Paulson RJ, Sauer MV, Lobo RA. 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