{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:03:38Z","timestamp":1789535018453,"version":"build-2803163510"},"reference-count":41,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pingdingshan College PhD Startup Fund","award":["PXY-BSQD-2026019"],"award-info":[{"award-number":["PXY-BSQD-2026019"]}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2023YFD1801101"],"award-info":[{"award-number":["2023YFD1801101"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shaanxi Livestock and Poultry Breeding Double-chain Fusion Key Project","award":["2022GD-TSLD-46"],"award-info":[{"award-number":["2022GD-TSLD-46"]}]},{"DOI":"10.13039\/100016692","name":"Key R&D Program of Ningxia Hui Autonomous Region","doi-asserted-by":"crossref","award":["2018BBF33001"],"award-info":[{"award-number":["2018BBF33001"]}],"id":[{"id":"10.13039\/100016692","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Successful embryo implantation necessitates formation of a complex and tight connection between a well-developed embryo and highly receptive endometrium. Type I interferon IFN-\u03c4 is a pregnancy recognition signal in ruminants that promotes the establishment of endometrial receptivity. However, the mechanisms that underpin this process largely remain unknown. Previous CUT&amp;Tag assays revealed that XBP1s preferentially targets genes in the glycolytic pathway. In this study, we found that IFN-\u03c4 significantly inhibited glycolysis and lactate production during peri-implantation. In addition, overexpression of XBP1s reversed the inhibition of glycolysis by IFN-\u03c4 and promoted expression of glycolysis rate-limiting enzymes (HK1, PFK-1, and PKM1) and lactate production. Dual-luciferase reporter and electrophoretic mobility shift assays demonstrated that XBP1s directly binds to the promoter of the ninth step gene of glycolysis, ENO1. Moreover, ENO1 and XBP1s exhibited congruent expression patterns, and both factors also reversed IFN-\u03c4-induced endometrial receptivity and inhibition of glycolysis. In contrast, knockdown of ENO1 enhanced the effects of IFN-\u03c4. Interestingly, lactate also inhibited the establishment of endometrial receptivity and PGES expression. In conclusion, our data suggest that XBP1s negatively regulates endometrial function through the transcriptional regulation of ENO1-promoted lactate production. This study provides key insights into the mechanisms by which XBP1s acts in female reproductive development.<\/jats:p>","DOI":"10.3390\/cells15181656","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:34:01Z","timestamp":1789378441000},"page":"1656","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcription Factor XBP1s Impairs Endometrial Receptivity by Promoting ENO1-Mediated Glycolysis and Lactate Production"],"prefix":"10.3390","volume":"15","author":[{"given":"Kangkang","family":"Gao","sequence":"first","affiliation":[{"name":"School of Medicine, Pingdingshan University, Pingdingshan 467000, China"},{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Xianyang 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Si","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Xianyang 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, Pingdingshan University, Pingdingshan 467000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijie","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine, Pingdingshan University, Pingdingshan 467000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Medicine, Pingdingshan University, Pingdingshan 467000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6815-4418","authenticated-orcid":false,"given":"Pengfei","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Xianyang 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3800-5013","authenticated-orcid":false,"given":"Huatao","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Xianyang 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhua","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Medicine, Pingdingshan University, Pingdingshan 467000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Xianyang 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Matsuno, Y., and Imakawa, K. (2025). Biological Aging and Uterine Fibrosis in Cattle: Reproductive Trade-Offs from Enhanced Productivity. Cells, 14.","DOI":"10.3390\/cells14130955"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100796","DOI":"10.1016\/j.animal.2023.100796","article-title":"Review: Implantation and placentation in ruminants","volume":"17","author":"Davenport","year":"2023","journal-title":"Animal"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-3-319-15856-3_7","article-title":"Implantation and Establishment of Pregnancy in Ruminants","volume":"216","author":"Spencer","year":"2015","journal-title":"Adv. Anat. Embryol. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"F33","DOI":"10.1530\/REP-17-0432","article-title":"Interferon-tau and fertility in ruminants","volume":"154","author":"Forde","year":"2017","journal-title":"Reproduction"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e20200048","DOI":"10.1590\/1984-3143-ar2020-0048","article-title":"Conceptus-modulated innate immune function during early pregnancy in ruminants: A review","volume":"18","author":"Rocha","year":"2021","journal-title":"Anim. Reprod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1095\/biolreprod.112.100438","article-title":"Intraluteal prostaglandin biosynthesis and signaling are selectively directed towards PGF2alpha during luteolysis but towards PGE2 during the establishment of pregnancy in sheep","volume":"87","author":"Lee","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/1477-7827-1-58","article-title":"Effects of the estrous cycle, pregnancy and interferon tau on expression of cyclooxygenase two (COX-2) in ovine endometrium","volume":"1","author":"Kim","year":"2003","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1262\/jrd.2016-176","article-title":"Estrous cycle stage-dependent manner of type I interferon-stimulated genes induction in the bovine endometrium","volume":"63","author":"Shirozu","year":"2017","journal-title":"J. Reprod. Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/s41392-026-02600-z","article-title":"Endoplasmic reticulum stress in disease pathogenesis: Its implications for therapy","volume":"11","author":"Wei","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s10735-013-9552-1","article-title":"GRP78 expression and regulation in the mouse uterus during embryo implantation","volume":"45","author":"Lin","year":"2014","journal-title":"J. Mol. Histol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.1002\/jcp.26210","article-title":"C-C motif chemokine ligand 23 abolishes ER stress- and LPS-induced reduction in proliferation of bovine endometrial epithelial cells","volume":"233","author":"Lim","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"158062","DOI":"10.1016\/j.phymed.2026.158062","article-title":"Echinacoside regulates the IRE1\/XBP1 signaling pathway through HSP72 to reduce endoplasmic reticulum stress and improve diabetic kidney disease","volume":"154","author":"Geng","year":"2026","journal-title":"Phytomedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.theriogenology.2022.07.014","article-title":"Spliced X-box binding protein 1 (XBP1s) protects spermatogonial stem cells (SSCs) from lipopolysaccharide (LPS)-induced damage by regulating the testicular microenvironment","volume":"191","author":"Xu","year":"2022","journal-title":"Theriogenology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.repbio.2016.10.003","article-title":"Tauroursodeoxycholic acid improves pre-implantation development of porcine SCNT embryo by endoplasmic reticulum stress inhibition","volume":"16","author":"Lin","year":"2016","journal-title":"Reprod. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1095\/biolreprod.113.113480","article-title":"Developmental competence of bovine early embryos depends on the coupled response between oxidative and endoplasmic reticulum stress","volume":"90","author":"Yoon","year":"2014","journal-title":"Biol. Reprod."},{"key":"ref_16","first-page":"208","article-title":"Expression and regulation of XBP1 in mouse uterus during early pregnancy","volume":"73","author":"Guo","year":"2021","journal-title":"Sheng Li Xue Bao"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"110451","DOI":"10.1016\/j.mehy.2020.110451","article-title":"Is there a relationship between early pregnancy loss and maternal serum human X-box binding protein 1 level?","volume":"146","author":"Uzun","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114398","DOI":"10.1016\/j.intimp.2025.114398","article-title":"The transcription factor XBP1 regulates mitochondrial remodel and autophagy in spontaneous abortion","volume":"152","author":"He","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/s41419-026-08646-9","article-title":"Glioblastoma cells that evade chemoradiotherapy-induced cell death exhibit a bifurcated glycolytic program","volume":"17","author":"Martell","year":"2026","journal-title":"Cell Death Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.1038\/s41467-026-69388-y","article-title":"Lactate derived from macrophages drives skin dermal fibroblasts phenotypic remodeling via MCT1-primed histone H3 lysine 23 lactylation in hypertrophic scar","volume":"17","author":"Yuan","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"107451","DOI":"10.1016\/j.pharmthera.2019.107451","article-title":"Lactate\/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon","volume":"206","author":"Brown","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1093\/cvr\/cvae058","article-title":"Stem cell factor and cKIT modulate endothelial glycolysis in hypoxia","volume":"120","author":"Jeong","year":"2024","journal-title":"Cardiovasc. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"P1137","DOI":"10.1016\/j.cmet.2022.06.008","article-title":"Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells","volume":"34","author":"Elia","year":"2022","journal-title":"Cell Metab."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhang, T., Chen, L., Kueth, G., Shao, E., Wang, X., Ha, T., Williams, D.L., Li, C., Fan, M., and Yang, K. (2024). Lactate\u2019s impact on immune cells in sepsis: Unraveling the complex interplay. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1483400"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4981","DOI":"10.1038\/s41467-022-32521-8","article-title":"Lactate increases stemness of CD8\u2009+\u2009T cells to augment anti-tumor immunity","volume":"13","author":"Feng","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.theriogenology.2023.07.014","article-title":"Downregulation of XBP1s aggravates lipopolysaccharide-induced inflammation by promoting NF-\u03baB and NLRP3 pathways\u2019 activation in goat endometrial epithelial cells","volume":"210","author":"Gao","year":"2023","journal-title":"Theriogenology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/biolre\/ioy044","article-title":"CREB3 regulatory factor -mTOR-autophagy regulates goat endometrial function during early pregnancy","volume":"98","author":"Yang","year":"2018","journal-title":"Biol. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5943","DOI":"10.1038\/s41598-024-84461-6","article-title":"ERS regulates endometrial epithelial cell autophagy through XBP1s-mediated activation of the PI3K\/AKT pathway","volume":"15","author":"Gao","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"C231","DOI":"10.1152\/ajpcell.00267.2021","article-title":"Circadian clock regulates granulosa cell autophagy through NR1D1-mediated inhibition of ATG5","volume":"322","author":"Zhang","year":"2022","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.gene.2017.08.026","article-title":"The developmental transcriptome landscape of receptive endometrium during embryo implantation in dairy goats","volume":"633","author":"Zhang","year":"2017","journal-title":"Gene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s12964-025-02050-0","article-title":"Transcription factor XBP1s promotes endometritis-induced epithelial-mesenchymal transition by targeting MAP3K2, a key gene in the MAPK\/ERK pathway","volume":"23","author":"Gao","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e10386","DOI":"10.1002\/advs.202410386","article-title":"METTL14-Mediated M6A Modification of LINC01094 Induces Glucose Metabolic Reprogramming in Breast Cancer by Recruiting the PKM2\/JMJD5 Complex","volume":"12","author":"Wang","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3892\/ijmm.2025.5562","article-title":"Lactate and lactylation in the kidneys: Current advances and prospects (Review)","volume":"56","author":"Li","year":"2025","journal-title":"Int. J. Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109195","DOI":"10.1016\/j.celrep.2021.109195","article-title":"Type I interferon decreases macrophage energy metabolism during mycobacterial infection","volume":"35","author":"Olson","year":"2021","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wald, M.E., Sieg, M., Schilling, E., Binder, M., Vahlenkamp, T.W., and Claus, C. (2022). The Interferon Response Dampens the Usutu Virus Infection-Associated Increase in Glycolysis. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.823181"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"gaag037","DOI":"10.1093\/molehr\/gaag037","article-title":"How decidualization dysregulation reshapes the nanomechanics of endometrial stromal cells","volume":"32","author":"Schafir","year":"2026","journal-title":"Mol. Hum. Reprod."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e0306822","DOI":"10.1128\/mbio.03068-22","article-title":"The IRE1\u03b1-XBP1 Signaling Axis Promotes Glycolytic Reprogramming in Response to Inflammatory Stimuli","volume":"14","author":"English","year":"2023","journal-title":"mBio"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1111\/febs.14776","article-title":"IRE1\u03b1 is critical for Kaempferol-induced neuroblastoma differentiation","volume":"286","author":"Abdullah","year":"2019","journal-title":"FEBS J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s41392-022-01151-3","article-title":"Lactate metabolism in human health and disease","volume":"7","author":"Li","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3428","DOI":"10.1038\/s41467-021-23827-0","article-title":"Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk","volume":"12","author":"Wang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e83299","DOI":"10.7554\/eLife.83299","article-title":"Glycolytic flux-signaling controls mouse embryo mesoderm development","volume":"11","author":"Miyazawa","year":"2022","journal-title":"eLife"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1656\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:26:13Z","timestamp":1789532773000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1656"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":41,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15181656"],"URL":"https:\/\/doi.org\/10.3390\/cells15181656","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]}}}