Insulin receptor substrate 2 regulates placental syncytiotrophoblast differentiation at the maternal-fetal interface

trophoblast stem cells, we show that IRS2 deficiency impairs upregulation of the SynT-II regulators Pparγ and Gcm1, disrupting SynT-II differentiation and sinusoidal trophoblast giant cell specification. Mechanistically, IRS2 relays insulin-like growth factor (IGF) signals through phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways to coordinate trophoblast proliferation, differentiation, and vascular morphogenesis. Human trophoblast stem cell differentiation and organoid analyses reveal IRS2 enrichment in the human syncytiotrophoblast (STB), indicating conserved expression at the human maternal-fetal interface.