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To resolve the molecular architecture of sPE, here we integrated DNA methylation and proteomic profiling from a multi-ethnic cohort of 444 placentas from the Hawaii Biorepository (HiBR), including 169 sPE cases, matched preterm controls and full-term controls. To address cellular heterogeneity in bulk placental tissue, we developed HOMED (Hierarchically Optimized Methylation Deconvolution), a single-cell-guided hierarchical framework for inferring placental cell-type composition from DNA methylation data. HOMED-adjusted integrative analyses identified extensive subtype-specific alterations involving hypoxia, angiogenesis, immune activation, trophoblast differentiation and metabolic remodeling. Molecular stratification revealed two reproducible sPE subtypes with divergent placental aging trajectories. One subtype exhibited a pre-mature placental state marked by accelerated placental aging, whereas the other displayed slower accelerated placental aging but a substantially increased risk of small-for-gestational-age birth (P = 0.028). These subtypes were independently replicated across six external cohorts and further supported by proteomic signatures achieving a classification accuracy of 0.88. Integrative epigenomic and proteomic analyses linked the growth-restricted subtype to hypoxia-associated glycolytic remodeling, suggesting distinct pathogenic mechanisms underlying clinically diagnosed sPE. Together, our findings redefine severe preeclampsia as a biologically heterogeneous placental disorder composed of molecularly distinct subtypes with divergent aging trajectories and fetal growth outcomes, providing a framework for mechanism-based stratification and precision obstetric medicine.<\/jats:p>","DOI":"10.64898\/2026.06.02.26354756","type":"posted-content","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:40:18Z","timestamp":1780594818000},"source":"Crossref","is-referenced-by-count":1,"title":["Placental molecular subtypes of severe preeclampsia reveal divergent aging trajectories and fetal growth outcomes"],"prefix":"10.64898","author":[{"given":"Yuheng","family":"Du","sequence":"first","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula A","family":"Benny","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Hawaii, Honolulu, HI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shayanki","family":"Lahiri","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadhl M.","family":"AlAkwaa","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianhui","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuansen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Washington University in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron B","family":"Lassiter","sequence":"additional","affiliation":[{"name":"University of Hawaii Cancer Center, Honolulu, HI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Astern","sequence":"additional","affiliation":[{"name":"University of Hawaii Biorepository, John A. 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