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bioRxiv · 10.64898/2026.11.09.765381

Longitudinal miRNA-mRNA Profiling Reveals Network Reorganization in Preeclampsia

Mirzakhani, H.·Jung, C.·Lu, Z.·Handy, D. E.·Loscalzo, J.·Weiss, S. T.
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Abstract

Background: Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity. Temporal dynamics of molecular dysregulation across pregnancy remain poorly understood. We performed longitudinal RNA sequencing of maternal whole blood to characterize miRNA-mRNA regulatory network evolution in PE. Methods: Whole-blood samples from early (M1: 10-18 weeks) and late pregnancy (M2: 32-38 weeks) were analyzed from 43 PE cases and 106 normotensive controls, including 109 paired samples (36 PE cases, 73 controls). Differential expression, temporal classification, pathway enrichment, and miRNA-mRNA network integration were performed. Placental expression support was assessed using internal RNA-seq and public databases. Key miRNA-mRNA interactions were experimentally validated in HTR-8/SVneo trophoblast cells. Results: PE exhibited marked temporal reorganization of miRNA-mRNA networks, with strongly opposing temporal effect sizes across overlapping miRNA and mRNA features (Spearman {rho} = -0.82, P < 0.0001). PI3K/AKT/mTORC1 signaling showed biphasic reversal (NES = +1.46, FDR = 0.028 at M1; NES = -1.64, FDR = 0.025 at M2), and heme-metabolism programs showed progressive suppression (2.1-fold NES intensification; FDR < 0.05 at both timepoints). Network analysis identified 29 high-confidence biphasic miRNA-mRNA pairs, including convergent targeting of ADGRA2 by three miRNAs and HSD17B1 by three miRNAs. miR-101-3p overexpression reduced DEPP1 mRNA (~40%) and protein (~26%) in trophoblast cells (P < 0.01), supporting a FOXO-DEPP1 axis. Blood-derived pairs showed pathway convergence with placental VGLL3-centered programs (PI3K/AKT, FOXO, TGF-{beta}, trophoblast differentiation). Conclusions: PE is associated with predominantly stage-specific or biphasic miRNA-mRNA network reorganization, with PI3K/AKT/mTORC1 dynamic remodeling and progressive heme-metabolism suppression. These findings support gestational-age-specific biomarker development and identify regulatory axes, including miR-101-3p [->] DEPP1, for mechanistic investigation.

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Mirzakhani, H., Jung, C., Lu, Z., Handy, D. E., Loscalzo, J., Weiss, S. T.. 2026-11-13. Longitudinal miRNA-mRNA Profiling Reveals Network Reorganization in Preeclampsia. https://doi.org/10.64898/2026.11.09.765381

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