Targeting FKBP51 prevents stress-induced preterm birth

Preterm birth (PTB) is a major cause of perinatal morbidity and mortality, with maternal stress-related disorders linked to idiopathic PTB (iPTB). At the maternal-fetal interface, decidualized stromal cells (DSCs), which exclusively express the progesterone receptor (PR), play key roles in maintaining pregnancy and initiating labor. FKBP51, expressed by DSCs, inhibits transcriptional activity of glucocorticoid and PR receptors and is associated with stress-related diseases. We previously found that iPTB specimens show increased FKBP51 levels and enhanced FKBP51-PR interactions in DSCs nuclei. Mice lacking Fkbp5 exhibit prolonged gestation and are resistant to stress-induced PTB, suggesting FKBP51's role in iPTB. With no FDA-approved treatment for PTB, we hypothesized that inhibiting FKBP51 could prevent iPTB. Our current results show that 15dPGJ2 reduces FKBP51 levels and FKBP51-PR interactions in cultured cells. Maternal stress increases uterine Fkbp5, Oxtr, and Akr1c18 expression, shortening gestation. However, 15dPGJ2 treatment reduces Fkbp51, Oxtr, and Ptgs2 levels, preventing stress-induced PTB. Notably, co-treatment with 15dPGJ2 and progesterone or R5020 produced the most significant effects, suggesting 15dPGJ2 alone or with progestins may be a promising PTB therapy.