A transferable trophoblast-centered transcriptional axis shared by preeclampsia and fetal growth restriction across public cohorts.

INTRODUCTION

Preeclampsia (PE) and fetal growth restriction (FGR) are clinically distinct but biologically overlapping placental insufficiency syndromes. Whether they share a transferable upstream regulatory program across cohorts and placental cell compartments remains unclear.

METHODS

We analyzed public placental transcriptomes with a regulator-centered framework. Recurrent regulators across PE, IUGR, and PEIUGR were identified in GSE114691, and a fixed axis from their downstream targets was projected unchanged into villous RNA-seq (GSE203507), microarray (GSE147776), and single-cell RNA-seq (GSE173193).

RESULTS

Discovery defined a HIF1A-activation/GBX2-repression core and an axis of 332 up and 191 down targets. Axis scores were elevated in PE, IUGR, and PEIUGR, strongest in overlap phenotypes, and directionally reproduced in external villous RNA-seq (strongest in EOPE + FGR), with only weak microarray support. In single-cell data, the axis localized mainly to trophoblast-related compartments rather than immune/myeloid cells.

DISCUSSION: These findings support a transferable trophoblast-centered placental regulatory axis consistent with convergent insufficiency, while remaining computational and hypothesis-generating pending experimental validation.