Syncytiotrophoblast differentiation defects drive ER stress and reprogram placental PSG1 glycosylation in preeclampsia

During pregnancy, placenta-derived proteins such as pregnancy-specific glycoprotein 1 (PSG1) enter the maternal circulation, providing a window into placental health and enabling liquid biopsy strategies for monitoring pregnancy disorders. PSG1, a highly glycosylated protein secreted by syncytiotrophoblast (STB) cells, reflects trophoblast differentiation status. Circulating PSG1 levels are reduced in early-onset preeclampsia (PE), but how PSG1 glycosylation is altered in this condition remains unclear. Here, we show by liquid chromatography-tandem mass spectrometry that native PSG1 purified from healthy and early-onset PE pregnancies carries an O-linked glycan in its N domain in addition to diverse N-linked glycans. In PE, PSG1 N-glycans displayed a shift toward increased oligomannose structures and reduced sialylation. Induction of endoplasmic reticulum (ER) stress in primary STBs altered the glycosylation enzyme machinery, and single-nucleus transcriptomic data indicated a reduced contribution of mature STB populations in PE, consistent with an immature STB-like glycoprotein signature. Altered N-glycosylation increased binding to mannose and asialoglycoprotein receptors and cellular uptake, suggesting enhanced hepatic clearance as a possible explanation for reduced circulating PSG1 levels in PE. Our data link ER stress during STB differentiation to altered glycoprotein maturation and identify PSG1 glycosylation as a readout of a stress-impaired STB in PE. Glycan features of circulating placental proteins could therefore provide information beyond protein levels alone and complement liquid biopsy approaches.