{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T08:10:12Z","timestamp":1773648612575,"version":"3.50.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Shandong Province Natural Science Foundation","doi-asserted-by":"crossref","award":["R2023QH077"],"award-info":[{"award-number":["R2023QH077"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shandong Province Medical and Health Technology Development Plan Project","award":["202205020216"],"award-info":[{"award-number":["202205020216"]}]},{"name":"Qingdao Natural Science Foundation for Young Scholars Project","award":["23-2-1-35-zyyd-jch"],"award-info":[{"award-number":["23-2-1-35-zyyd-jch"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-15533-4","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T11:13:10Z","timestamp":1754910790000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["ELABELA targets the MEK\/ERK axis to enhance trophoblast invasion in early-onset preeclampsia"],"prefix":"10.1038","volume":"15","author":[{"given":"Lijing","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningning","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhanping","family":"Weng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"15533_CR1","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1097\/MNH.0000000000000857","volume":"32","author":"S Gupta","year":"2023","unstructured":"Gupta, S. et al. Hypertension in pregnancy: what we now know. Curr. Opin. Nephrol. Hypertens. 32, 153\u2013164. https:\/\/doi.org\/10.1097\/MNH.0000000000000857 (2023).","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"15533_CR2","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3892\/ijmm.2025.5499","volume":"55","author":"D Marzioni","year":"2025","unstructured":"Marzioni, D. et al. Importance of STAT3 signaling in preeclampsia (Review). Int. J. Mol. Med. 55, 58. https:\/\/doi.org\/10.3892\/ijmm.2025.5499 (2025).","journal-title":"Int. J. Mol. Med."},{"key":"15533_CR3","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.3390\/antiox13101234","volume":"13","author":"L Annesi","year":"2024","unstructured":"Annesi, L. et al. The role of Xanthine oxidase in pregnancy complications: A systematic review. Antioxid. (Basel). 13, 1234. https:\/\/doi.org\/10.3390\/antiox13101234 (2024).","journal-title":"Antioxid. (Basel)"},{"key":"15533_CR4","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1097\/HJH.0000000000003472","volume":"41","author":"F 4 Piani","year":"2023","unstructured":"4 Piani, F. et al. Serum uric acid to creatinine ratio and risk of preeclampsia and adverse pregnancy outcomes. J. Hypertens. 41, 1333\u20131338. https:\/\/doi.org\/10.1097\/HJH.0000000000003472 (2023).","journal-title":"J. Hypertens."},{"key":"15533_CR5","doi-asserted-by":"publisher","first-page":"6091","DOI":"10.1002\/jcp.27344","volume":"234","author":"G Tossetta","year":"2019","unstructured":"Tossetta, G. et al. Pre-eclampsia onset and SPARC: A possible involvement in placenta development. J. Cell. Physiol. 234, 6091\u20136098. https:\/\/doi.org\/10.1002\/jcp.27344 (2019).","journal-title":"J. Cell. Physiol."},{"key":"15533_CR6","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1159\/000525851","volume":"87","author":"A Shigemitsu","year":"2022","unstructured":"Shigemitsu, A. et al. Hypoxia promotes extravillous trophoblast cell invasion through the Hypoxia-Inducible factor Urokinase-Type plasminogen activator receptor pathway. Gynecol. Obstet. Invest. 87, 232\u2013241. https:\/\/doi.org\/10.1159\/000525851 (2022).","journal-title":"Gynecol. Obstet. Invest."},{"key":"15533_CR7","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1124\/pr.119.017533","volume":"71","author":"C Read","year":"2019","unstructured":"Read, C. et al. International union of basic and clinical pharmacology. CVII. Structure and pharmacology.of the Apelin receptor with a recommendation that elabela\/toddler is a second endogenous peptide ligand. Pharmacol. Rev. 71, 467\u2013502. https:\/\/doi.org\/10.1124\/pr.119.017533 (2019).","journal-title":"Pharmacol. Rev."},{"key":"15533_CR8","doi-asserted-by":"publisher","first-page":"102076","DOI":"10.1016\/j.arr.2023.102076","volume":"91","author":"R Monastero","year":"2023","unstructured":"Monastero, R. et al. A promising therapeutic peptide and preventive\/diagnostic biomarker for age-related diseases: the elabela\/apela\/toddler peptide. Ageing Res. Rev. 91, 102076. https:\/\/doi.org\/10.1016\/j.arr.2023.102076 (2023).","journal-title":"Ageing Res. Rev."},{"key":"15533_CR9","doi-asserted-by":"publisher","unstructured":"Perjes, A. et al. Characterization of apela, a novel endogenous ligand of Apelin receptor, in the adult heart. Basic Res. Cardiol. 111 (2). https:\/\/doi.org\/10.1007\/s00395-015-0521-6 (2016).","DOI":"10.1007\/s00395-015-0521-6"},{"key":"15533_CR10","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.cytogfr.2019.03.003","volume":"46","author":"D Eberle","year":"2019","unstructured":"Eberle, D. et al. Elabela and Apelin actions in healthy and pathological pregnancies. Cytokine Growth Factor Rev. 46, 45\u201353. https:\/\/doi.org\/10.1016\/j.cytogfr.2019.03.003 (2019).","journal-title":"Cytokine Growth Factor Rev."},{"key":"15533_CR11","doi-asserted-by":"publisher","first-page":"E773","DOI":"10.1152\/ajpendo.00383.2018","volume":"316","author":"L Zhou","year":"2019","unstructured":"Zhou, L. et al. ELABELA, as a potential diagnostic biomarker of preeclampsia, regulates abnormally shallow placentation via APJ. American journal of physiology. Endocrinol. Metabolism. 316, E773\u2013E781. https:\/\/doi.org\/10.1152\/ajpendo.00383.2018 (2019).","journal-title":"Endocrinol. Metabolism"},{"key":"15533_CR12","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.placenta.2021.02.002","volume":"106","author":"J Ma","year":"2021","unstructured":"Ma, J. et al. ELABELA alleviates syncytiotrophoblast hypoxia\/reoxygenation injury and preeclampsia-like symptoms in mice by reducing apoptosis. Placenta 106, 30\u201339. https:\/\/doi.org\/10.1016\/j.placenta.2021.02.002 (2021).","journal-title":"Placenta"},{"key":"15533_CR13","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.preghy.2022.10.005","volume":"30","author":"D Liu","year":"2022","unstructured":"Liu, D. et al. Exposure to higher concentrations of exogenous ELABELA causes HTR-8\/SVneo trophoblast cell dysfunction: A possible pathogenesis of pre-eclampsia. Pregnancy Hypertens. 30, 181\u2013188. https:\/\/doi.org\/10.1016\/j.preghy.2022.10.005 (2022).","journal-title":"Pregnancy Hypertens."},{"key":"15533_CR14","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1001\/jamainternmed.2024.0276","volume":"184","author":"C Crump","year":"2024","unstructured":"Crump, C. et al. Adverse pregnancy outcomes and Long-Term mortality in women. JAMA Intern. Med. 184, 631\u2013640. https:\/\/doi.org\/10.1001\/jamainternmed.2024.0276 (2024).","journal-title":"JAMA Intern. Med."},{"key":"15533_CR15","doi-asserted-by":"publisher","unstructured":"Sharma, B. et al. Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts. Developmental cell 42, 655\u2013666 e653, (2017). https:\/\/doi.org\/10.1016\/j.devcel.2017.08.008","DOI":"10.1016\/j.devcel.2017.08.008"},{"key":"15533_CR16","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1021\/acs.jmedchem.0c01547","volume":"64","author":"K Tran","year":"2021","unstructured":"Tran, K. et al. Structure-Activity relationship and bioactivity of short analogues of ELABELA as agonists of the Apelin receptor. J. Med. Chem. 64, 602\u2013615. https:\/\/doi.org\/10.1021\/acs.jmedchem.0c01547 (2021).","journal-title":"J. Med. Chem."},{"key":"15533_CR17","doi-asserted-by":"publisher","first-page":"eadd2488","DOI":"10.1126\/sciadv.add2488","volume":"8","author":"J Stock","year":"2022","unstructured":"Stock, J. et al. A self-generated toddler gradient guides mesodermal cell migration. Sci. Adv. 8, eadd2488. https:\/\/doi.org\/10.1126\/sciadv.add2488 (2022).","journal-title":"Sci. Adv."},{"key":"15533_CR18","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1038\/s41440-018-0193-3","volume":"42","author":"Y Liu","year":"2019","unstructured":"Liu, Y. et al. The biological function of ELABELA and APJ signaling in the cardiovascular system and pre-eclampsia. Hypertens. Research: Official J. Japanese Soc. Hypertens. 42, 928\u2013934. https:\/\/doi.org\/10.1038\/s41440-018-0193-3 (2019).","journal-title":"Hypertens. Research: Official J. Japanese Soc. Hypertens."},{"key":"15533_CR19","doi-asserted-by":"publisher","unstructured":"Dawid, M. et al. Role in placental function, pregnancy, and foetal Development-An overview. Cells 11 https:\/\/doi.org\/10.3390\/cells11010099 (2021).","DOI":"10.3390\/cells11010099"},{"key":"15533_CR20","doi-asserted-by":"publisher","unstructured":"Respekta, N. et al. The apelinergic system: apelin, ELABELA, and APJ action on cell apoptosis: Anti-Apoptotic or Pro-Apoptotic effect?? cells 12, (2022). https:\/\/doi.org\/10.3390\/cells12010150","DOI":"10.3390\/cells12010150"},{"key":"15533_CR21","doi-asserted-by":"publisher","first-page":"2759","DOI":"10.1096\/fj.201801163R","volume":"33","author":"J Canfield","year":"2019","unstructured":"Canfield, J. et al. Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration. FASEB Journal: Official Publication Federation Am. Soc. Experimental Biology. 33, 2759\u20132769. https:\/\/doi.org\/10.1096\/fj.201801163R (2019).","journal-title":"FASEB Journal: Official Publication Federation Am. Soc. Experimental Biology"},{"key":"15533_CR22","doi-asserted-by":"publisher","first-page":"109233","DOI":"10.1016\/j.celrep.2021.109233","volume":"35","author":"SA Khan","year":"2021","unstructured":"Khan, S. A. et al. Probing the signaling requirements for Naive human pluripotency by high-throughput chemical screening. Cell. Rep. 35, 109233. https:\/\/doi.org\/10.1016\/j.celrep.2021.109233 (2021).","journal-title":"Cell. Rep."},{"key":"15533_CR23","doi-asserted-by":"publisher","unstructured":"Bayerl, J. et al. Principles of signaling pathway modulation for enhancing human naive pluripotency induction. Cell stem cell 28, 1549\u20131565 e1512, (2021). https:\/\/doi.org\/10.1016\/j.stem.2021.04.001","DOI":"10.1016\/j.stem.2021.04.001"},{"key":"15533_CR24","doi-asserted-by":"publisher","first-page":"873614","DOI":"10.3389\/fphar.2022.873614","volume":"13","author":"X Wang","year":"2022","unstructured":"Wang, X. et al. ELA-11 protects the heart against oxidative stress injury induced apoptosis through ERK\/MAPK and PI3K\/AKT signaling pathways. Front. Pharmacol. 13, 873614. https:\/\/doi.org\/10.3389\/fphar.2022.873614 (2022).","journal-title":"Front. Pharmacol."},{"key":"15533_CR25","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1186\/s13287-020-02063-1","volume":"11","author":"J Fu","year":"2020","unstructured":"Fu, J. et al. ELABELA ameliorates hypoxic\/ischemic-induced bone mesenchymal stem cell apoptosis via alleviation of mitochondrial dysfunction and activation of PI3K\/AKT and ERK1\/2 pathways. Stem Cell Res. Ther. 11, 541. https:\/\/doi.org\/10.1186\/s13287-020-02063-1 (2020).","journal-title":"Stem Cell Res. Ther."},{"key":"15533_CR26","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/j.devcel.2013.11.002","volume":"27","author":"SC Chng","year":"2013","unstructured":"Chng, S. C. et al. ELABELA: a hormone essential for heart development signals via the Apelin receptor. Dev. Cell. 27, 672\u2013680 (2013).","journal-title":"Dev. Cell"},{"key":"15533_CR27","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1161\/CIRCRESAHA.124.325699","volume":"137","author":"KG Tlaye","year":"2025","unstructured":"Tlaye, K. G. et al. Pharmacogenomics and pharmacokinetics of aspirin in preeclampsia prevention. Circ. Res. 137, 69\u201382. https:\/\/doi.org\/10.1161\/CIRCRESAHA.124.325699 (2025).","journal-title":"Circ. Res."},{"key":"15533_CR28","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1093\/humupd\/dmaa017","volume":"26","author":"Y Abbas","year":"2020","unstructured":"Abbas, Y. et al. Investigation of human trophoblast invasion in vitro. Hum. Reprod. Update. 26, 501\u2013513. https:\/\/doi.org\/10.1093\/humupd\/dmaa017 (2020).","journal-title":"Hum. Reprod. Update"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-15533-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-15533-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-15533-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T20:14:32Z","timestamp":1757362472000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-15533-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,11]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["15533"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-15533-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,11]]},"assertion":[{"value":"26 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Ethics Committee of Qingdao Municipal Hospital (2024-KY-018).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research involving human participants and\/or animals"}},{"value":"Informed consent Informed consent was signed by all pregnant women.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}],"article-number":"29357"}}