Progesterone receptor antagonism by mifepristone impairs trophoblast stemness and promotes apoptosis through upregulation of PDCD4.

backgroundTrophoblast cells are a critical component of retained products of conception (RPOC). While mifepristone is widely used as a non-invasive treatment for RPOC, its precise molecular mechanisms in trophoblast regulation remain poorly defined.

resultsThrough integrated in vitro and in vivo approaches using human trophoblast stem cells (TSCs), HTR8/SVneo cells, and placental villus explants, we demonstrated that mifepristone exerts its effects predominantly via progesterone receptor (PGR) antagonism rather than glucocorticoid receptor (GR) inhibition. PGR knockdown in TSCs and trophoblast organoids impaired trophoblast stemness. RNA-sequencing of PGR-knockdown TSCs revealed upregulated apoptosis and reduced self-renewal and differentiation abilility, identifying PDCD4 as a key downstream target. Functional experiments showed that PDCD4 overexpression recapitulated the mifepristone-induced trophoblast dysfunction, including diminished proliferation, migration, invasion, and stemness, as well as increased apoptosis. In vivo, mifepristone administration in pregnant mice elevated PDCD4 expression, enhanced placental apoptosis, and facilitated clearance of conception products.

conclusionsOur findings reveal that mifepristone impairs trophoblast function by antagonizing PGR and inducing PDCD4, thereby impairing stemness and promoting apoptosis. This mechanistic insight not only advances our understanding of mifepristone's action in RPOC treatment but also suggests broader clinical implications for targeting trophoblast function.