PIP₂ Accumulation in the Spongiotrophoblast Drives Trophoblast Apoptosis in Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by elevated maternal bile acids and an increased risk of adverse fetal outcomes. Although placental dysfunction is a key contributor to ICP pathogenesis, the underlying mechanisms remain incompletely understood. Here, we combined a Sprague-Dawley rat model of ICP with spatial metabolomics to delineate region-specific metabolic alterations within the placenta. Multivariate analysis revealed distinct metabolic signatures between ICP and control placentas, with pronounced reprogramming in trophoblast-enriched regions. Differential metabolite and pathway analyses identified significant perturbations in glycerophospholipid metabolism, pyruvate metabolism, phospholipase D signaling, and the tricarboxylic acid cycle. Notably, phosphatidic acid (PA) was broadly elevated, whereas its downstream product phosphatidylinositol 4,5-bisphosphate (PIP₂) exhibited spatially restricted accumulation in trophoblasts. Mechanistically, taurocholic acid exposure in HTR-8/SVneo cells induced upregulation of PIP5K1, leading to PIP₂ accumulation and increased trophoblast apoptosis via disruption of the Bcl-2/Bax balance. Silencing of PIP5K1 restored PIP₂ homeostasis and attenuated apoptosis. Importantly, these molecular alterations were recapitulated in placental tissues from ICP patients, confirming activation of the PIP5K1-PIP2 axis in vivo. Collectively, our findings identify a spatially resolved PA-PIP5K1-PIP₂ lipid signaling cascade that links bile acid-induced metabolic stress to trophoblast apoptosis and placental dysfunction in ICP.