Reducing early pregnancy loss by mitigating decidual ROS and ferroptosis

PROJECT SUMMARY It is estimated that 10-20% of all clinically recognized pregnancies will end before 12 weeks of gestation. While several risk factors are associated with this increased early pregnancy loss, uterine and endometrial factors remain a key area of investigation. Mammalian species with deep placentation, including humans, rats, mice, and some non-human primates, evolved specialized adaptations at the fetomaternal interface to accommodate deep trophoblast invasion. A critical component of this adaptation includes decidualization which is the reprogramming of endometrial stromal cells into functional decidual cells, a process that is uniquely characterized by resistance to oxidative stress. Decidual cells provide essential support to the developing blastocyst prior to placental formation, providing nutrients, growth factors, and protection from maternal immunological rejection. Accordingly, abnormal decidualization is strongly linked to early pregnancy loss and complications such as fetal growth restriction, preeclampsia, and preterm birth. In contrast to species without decidualization (i.e., marsupials), species capable of decidualization (e.g., humans and mice) developed unique mechanisms to resist the oxidative stress induced by decidualization. However, the molecular signals that underlie this resistance are not fully understood. We identified that the iron exporter, ferroportin (SLC40A1), and the antioxidant enzyme, glutathione peroxidase 4 (GPX4), are essential for decidualization and fertility. Together, SLC40A1 and GPX4 control iron homeostasis and prevent oxidative damage, particularly ferroptosis, a form of iron-induced cell death. Endometrial biopsies show that SLC40A1 and GPX4 increase during the secretory phase, and their knockdown impairs in vitro decidualization. Our preliminary data indicate that SLC40A1 and GPX4 work together to reduce lipid peroxidation and ferroptosis in decidualizing cells. Mice with conditional knockout (cKO) of SLC40A1 using progesterone receptor cre or GPX4 exhibit severe subfertility and infertility, respectively. Thus, we hypothesize that SLC40A1 and GPX4 are essential for fertility and decidualization by protecting endometrial stromal cells from oxidative stress during early pregnancy. Our proposed studies in this R01 align with the strategic goals of the Fertility and Infertility Branch at NICHD to address “the etiology of unexplained early pregnancy loss” and the “biological factors involved in pregnancy establishment.”