iProXProteomicsSongfang WuHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0017792000wusofa@126.comShanghai Xuhui Central HospitaliProXfalseGlycodelin binds PS to inhibit its aPC cofactor activityProtein S (PS) activity declines early in pregnancy, but current models based on estrogen-driven PROS1 suppression or C4b-binding protein binding cannot fully account for the disproportionate loss of PS-specific activity. We hypothesized that an unidentified plasma factor directly modulates PS function during gestation. Integrated proteomic profiling of 107 plasma samples revealed glycodelin, a decidua-derived glycoprotein, as the top candidate inversely correlated with PS-specific activity in the 1st trimester. Native PAGE and PS immunoprecipitation demonstrated a pregnancy-specific multimeric PS complex, which was most prominent when PS-specific activity was lowest in the 1st trimester. Glycodelin was exclusively enriched in 1st trimester PS immunoprecipitates and undetectable in nonpregnant controls. Direct binding between glycodelin and PS was confirmed by biolayer interferometry (KD=148 nM). Functionally, physiological concentrations of recombinant glycodelin selectively suppressed the activated protein C cofactor activity of PS by approximately 40% without impairing its tissue factor pathway inhibitor-mediated anti-FXa function. Domain mapping via cross-linking mass spectrometry as well as ELISA binding assay identified the EGF-like domains of PS as the critical interaction site for glycodelin, overlapping with the epitope recognized by anti-PS autoantibodies in patients with recurrent pregnancy loss (RPL). These findings establish glycodelin as a novel post-translational regulator that directly binds PS and attenuates its anticoagulant capacity in early pregnancy. By linking a key feto-maternal tolerance factor to hemostatic adaptation, our work reveals a previously unrecognized mechanism contributing to the hypercoagulable state of gestation and may provide new insights into the pathogenesis of RPL.Mon Jun 22 00:00:00 GMT+01:00 2026PXD0799599606