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Although impaired endometrial angiogenesis is thought to contribute to its pathogenesis, the underlying molecular mechanisms remain incompletely understood. This study aimed to investigate whether sphingolipid metabolism plays a role in the vascular dysfunction of CE patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Endometrial samples from control and CE patients were assessed for angiogenesis using immunohistochemistry. Sequencing data of endometrial tissues indicated dysregulation of sphingolipid metabolism in CE patients. ELISA revealed decreased levels of sphingosine-1-phosphate (S1P) in the endometrium of CE patients and in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs). Functional assays including tube formation, wound healing, and transwell invasion were performed to evaluate the effects of LPS and S1P on HUVECs. Western blotting was used to explore the signaling pathways through which S1P influences HUVECs function after LPS stimulation. RT-qPCR and Western blot analyses further suggested that the reduction in S1P under inflammatory conditions may be attributable to upregulation of sphingosine-1-phosphate phosphatase 2 (SGPP2). Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were employed to detect CEBPD binding to the SGPP2 promoter, and immunofluorescence was used to assess nuclear localization of relevant factors. Knockout experiments were conducted to validate the relationship among CEBPD, SGPP2, and endoplasmic reticulum (ER) stress. Finally, the effect of S1P on pregnancy outcomes was evaluated in a CE mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Microvessel density (MVD) and S1P levels were decreased in both CE patients and the CE mouse model. In HUVECs, LPS suppressed tube formation, migration, and invasion; these effects were reversed by exogenous S1P via the S1PR1-STAT3-VEGFA pathway. SGPP2, an S1P-degrading enzyme, was upregulated in CE endometrial tissues and in LPS-stimulated HUVECs. Mechanistically, the transcription factor CEBPD was shown to directly bind the SGPP2 promoter and promote its expression, a process dependent on PERK-eIF2\u03b1-mediated ER stress. In the mouse model, intrauterine administration of S1P attenuated endometrial inflammation, improved angiogenesis, and significantly reduced embryo resorption rates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings delineate a novel pathway linking inflammatory stress to aberrant angiogenesis in endometrium, in which ER stress-driven CEBPD activation transcriptionally upregulates SGPP2, creating a molecular nexus between inflammation and sphingolipid metabolism. This S1P signaling deficit compromises a critical angiogenic pathway necessary for vascular remodeling, which in turn disrupts endometrial receptivity and contributes to CE-associated reproductive failures.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-025-07558-0","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T09:04:53Z","timestamp":1765962293000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["CEBPD-mediated SGPP2 upregulation via PERK\/ER stress in endothelial cells disrupts S1P homeostasis and impairs angiogenesis in chronic endometritis"],"prefix":"10.1186","volume":"24","author":[{"given":"Yanjun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanying","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruochun","family":"Lian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianghui","family":"Diao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuye","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tailang","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"7558_CR1","first-page":"176","volume":"58","author":"SM Greenwood","year":"1981","unstructured":"Greenwood SM, Moran JJ. 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