VGLL3-centered network connects placental, vascular, and immune defects in preeclampsia.

Preeclampsia affects approximately 1 in 10 pregnancies, leading to severe complications and long-term health risks for both mother and offspring. While the etiology remains unclear, preeclampsia has been linked to both autoimmunity and the timing of menarche. Through human single-cell and spatial analyses, coupled with in vitro, in vivo, and ex vivo models, we demonstrate that VGLL3, a transcription co-regulator in the Hippo pathway, is upregulated in preeclamptic placentas. VGLL3 promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction, all of which contribute to pregnancy-related hypertension, fetal growth restriction, and offspring mortality. Our data reveal that VGLL3 acts upstream of preeclampsia-associated processes, including the production of sFLT1, a key biomarker of the disease. Notably, targeting VGLL3-either by genetic deletion in mouse placentas or through therapeutic inhibition in human placentas-protects against preeclampsia and alleviates disease pathology. These findings position VGLL3 as a promising novel therapeutic target for preeclampsia.