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Strong evidence supports placental dysfunction as central to preeclampsia; however, there is inadequate understanding of the precise pathogenesis of preeclampsia. In this study, we present a comprehensive multi\u2010omics analysis of early pregnancy placental biopsies (chorionic villus samples) from pregnancies that later developed preterm\/term preeclampsia, compared to normotensive controls. Using an integrative multivariate approach, we uncovered distinct molecular signatures associated with preeclampsia. Preterm preeclampsia was strongly associated with dysregulated lipoprotein metabolism, while term preeclampsia exhibited alterations in inflammatory pathways, Notch\/Kit signaling, and ribosome assembly. These results challenge the prevailing notion that term preeclampsia is unrelated to early placental pregnancy dysfunction. To validate our findings, we focused on melanophilin, a gene downregulated in the early pregnancy placenta of term preeclampsia. Melanophilin expression was reduced during cytotrophoblast syncytialization; however, excessive loss disrupted syncytiotrophoblast function, triggering the production of factors known to drive preeclampsia. Our study provides critical insights into the early pregnancy aberrations underlying preterm and term preeclampsia, paving the way for the development of predictive biomarkers and targeted preventative treatments. This work represents a significant step toward unraveling the complex etiology of preeclampsia and improving maternal and perinatal health outcomes.<\/jats:p>","DOI":"10.1002\/mco2.70784","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T07:23:49Z","timestamp":1779780229000},"source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010Omics Reveals Early Pregnancy Placental Dysfunction Associated With Preterm and Term Preeclampsia"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2440-6665","authenticated-orcid":false,"given":"Ellen","family":"Menkhorst","sequence":"first","affiliation":[{"name":"Department of Obstetrics Gynaecology and Newborn Health The University of Melbourne  Parkville Victoria Australia"},{"name":"Gynaecology Research Centre Royal Women's Hospital  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guannan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Gynaecology and Newborn Health The University of Melbourne  Parkville Victoria Australia"},{"name":"Gynaecology Research Centre Royal Women's Hospital  Parkville Victoria Australia"},{"name":"Melbourne Integrative Genomics School of Mathematics and Statistics The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimiao","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Gynaecology and Newborn Health The University of Melbourne  Parkville Victoria Australia"},{"name":"Gynaecology Research Centre Royal Women's Hospital  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leilani L.","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Gynaecology and Newborn Health The University of Melbourne  Parkville Victoria Australia"},{"name":"Gynaecology Research Centre Royal Women's Hospital  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9636-7963","authenticated-orcid":false,"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Gynaecology and Newborn Health The University of Melbourne  Parkville Victoria Australia"},{"name":"Gynaecology Research Centre Royal Women's Hospital  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argyro","family":"Syngelaki","sequence":"additional","affiliation":[{"name":"Fetal Medicine Foundation  London UK"},{"name":"Harris Birthright Research Centre for Fetal Medicine King's College Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swati","family":"Varshney","sequence":"additional","affiliation":[{"name":"Melbourne Mass Spectrometry and Proteomics Facility Bio21 Molecular Science &amp; Biotechnology Institute The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A.","family":"Williamson","sequence":"additional","affiliation":[{"name":"Melbourne Mass Spectrometry and Proteomics Facility Bio21 Molecular Science &amp; Biotechnology Institute The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology The University of Tokyo  Tokyo Japan"},{"name":"Department of Obstetrics and Gynecology Reproductive Medicine Chiba University  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Lorber","family":"Rolnik","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology Monash University  Melbourne Victoria Australia"},{"name":"Women's and Newborn Monash Health  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabricio","family":"da Silva Costa","sequence":"additional","affiliation":[{"name":"Maternal Fetal Medicine Unit Gold Coast University Hospital  Gold Coast Queensland Australia"},{"name":"School of Medicine and Dentistry Griffith University  Gold Coast Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kypros","family":"Nicolaides","sequence":"additional","affiliation":[{"name":"Fetal Medicine Foundation  London UK"},{"name":"Harris Birthright Research Centre for Fetal Medicine King's College Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim\u2010Anh","family":"L\u00ea Cao","sequence":"additional","affiliation":[{"name":"Melbourne Integrative Genomics School of Mathematics and Statistics The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evdokia","family":"Dimitriadis","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Gynaecology and Newborn Health The University of Melbourne  Parkville Victoria Australia"},{"name":"Gynaecology Research Centre Royal Women's Hospital  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-023-00417-6"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2013.05.005"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preghy.2021.09.008"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijgo.12802"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(24)00560-6"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l2381"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preghy.2014.02.001"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.01892"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-0528.1981.tb02222.x"},{"key":"e_1_2_11_11_1","first-page":"115","article-title":"Maternal Uterine Vascular Lesions in the Hypertensive Complications of Pregnancy","volume":"5","author":"Robertson W. 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