Subtype specific immune-metabolic reprogramming in preeclampsia revealed by multiomics and serum biomarkers.

Preeclampsia comprises early-onset (EOPE) and late-onset (LOPE) subtypes with distinct etiologies, placental pathology, and severity, but cellular/metabolic drivers and early biomarkers remain unclear. We integrated placental single-cell RNA-seq, spatial transcriptomics, and spatial metabolomics from EOPE, LOPE, and matched controls, and performed maternal serum metabolomics in a prospective cohort of 199 pregnancies. The scRNA-seq identified 14 cell types; Hofbauer cells and trophoblasts resolved into 7 and 3 subclusters. EOPE placentas showed increased macrophages and extravillous trophoblasts, reduced oxygen-transporting Hofbauer subtypes (HB_1, HB_6), and trophoblasts with heightened HIF-1, VEGF, and IGF signaling. LOPE preserved cellular composition but exhibited stronger inflammatory transcriptional programs. Spatial analyses indicated disrupted oxygen transport in EOPE and perturbed interferon-γ signaling and exosome secretion in LOPE. Metabolically, trophoblasts and Hofbauer cells displayed subtype-specific lipid-transport defects and mitochondrial dysfunction. Three early-pregnancy serum metabolites-phosphatidylcholine PC(22:5/0:0), 3-hydroxybutyric acid, and L-allothreonine-robustly predicted EOPE (AUC > 0.85). This study delineates preeclampsia as a spectrum of placental immune-metabolic disorders. Hofbauer cells and trophoblasts undergo subtype-specific transcriptional and metabolic remodeling in EOPE vs LOPE. Multi-omics-guided, noninvasive biomarkers enable early EOPE risk prediction, informing timely detection and intervention.