BAP1 dysregulation impairs trophoblast differentiation and contributes to placental dysfunction in preeclampsia

Preeclampsia, a life threatening hypertensive disorder of pregnancy, is a leading cause of maternal and perinatal morbidity and mortality. Its early onset form (EO PE), requiring delivery before 34 weeks of gestation, is particularly severe and closely linked to defective trophoblast differentiation. Here, we identify BRCA1-associated protein 1 (BAP1) and its cofactors ASXL2 and ASXL3 are upregulated in EO PE placentas. Enforced BAP1 expression in human trophoblast stem cells reinforced epithelial identity, enhanced adhesion, and impaired both extravillous trophoblast differentiation and syncytiotrophoblast formation. Integrated transcriptomic and proteomic analyses revealed suppression of lineage-specific pathways alongside maintenance of progenitor-like and pro-inflammatory signatures. In trophoblast organoids, excess of BAP1 disrupted syncytial maturation and induced interferon-driven pathways overlapping with EO PE transcriptomes. Together, these findings establish BAP1 as a key regulator of human trophoblast differentiation and implicate its dysregulation in the pathogenesis of EO PE, providing mechanistic insight into the cellular basis of placental dysfunction.