Cordycepin inhibits human extravillous trophoblast invasion by suppressing snail-mediated MMP2 expression

Invasion of extravillous trophoblast (EVT) cells is essential for establishing proper maternal-fetal circulation and ensuring successful pregnancy outcomes. Cordycepin (COR), a bioactive compound derived from Cordyceps spp., is an adenosine analog known to exert multiple beneficial effects on human health. Although COR has been reported to suppress invasiveness in various cancer cell types, its effect on human EVT cell invasion remains unclear. In the present study, we demonstrated that COR treatment did not affect the cell viability but significantly downregulated matrix metalloproteinase 2 (MMP2) expression in both the immortalized human EVT cell line HTR-8/SVneo and primary human EVT cells. Using specific adenosine receptor antagonists, we further showed that the inhibitory effect of COR on MMP2 expression was mediated by A₁, A_2A, and A₃ adenosine receptors. Mechanistically, COR activated ERK1/2 and AKT signaling pathways, but only AKT activation was required for the COR-induced downregulation of MMP2. In addition, COR suppressed the expression of the transcription factor Snail, which contributed to the downregulation of MMP2. Functionally, COR treatment inhibited EVT cell invasion, and this effect was mediated by MMP2 downregulation. These findings provide new insights into the molecular mechanisms by which COR regulates EVT cell invasiveness and highlight the potential implications of COR as a health supplement during pregnancy.