PSG9 is a pregnancy-specific glycoprotein with dual immunoregulatory and vascular functions critical for maternal-fetal tolerance. Mechanistically, PSG9 binds to the latency-associated peptide (LAP) of the small latent transforming growth factor-beta (TGF-β1) complex, directly activating TGF-β1 1. This activation stimulates naive CD4+ T cells to increase FoxP3 expression and promotes differentiation of FoxP3+ regulatory T cells, while also inducing TGF-β1 secretion from macrophages 1. PSG9 simultaneously reduces pro-inflammatory cytokine production (IL-2, IL-6) and promotes a suppressive CD4+LAP+FoxP3− T-cell subset 1. Additionally, PSG9 enhances store-operated calcium entry and nitric oxide release in endothelial cells through SOCE channel activation, supporting vascular health 2. Clinically, PSG9 serves as a biomarker for pregnancy complications. Circulating PSG9 levels are significantly elevated before preeclampsia onset and in established disease with severe features 3, though interestingly serum PSG9 is decreased in preeclamptic patients 2. PSG9 is also downregulated in recurrent pregnancy loss, particularly in late pregnancy loss 4. PSG9 expression is regulated by retroelement LTR8B and influences trophoblast syncytialization 5. These findings establish PSG9 as a key regulator of immune tolerance and endothelial function essential for successful pregnancy.