Implications for iron homeostasis and ferroptosis in early pregnancy and endometriosis

Baylor College Of Medicine, Houston TX

Investigators

Abstract

Endometriosis, affecting approximately 10% of women of reproductive age, poses significant challenges due to its association with increased infertility and pregnancy complications. Dysregulated iron homeostasis and oxidative stress have been identified as significant contributors to these adverse reproductive outcomes. Iron, essential for critical cellular functions such as energy production and DNA synthesis, can lead to oxidative stress when present in excess, producing reactive oxygen species (ROS) that damage cellular structures. SLC40A1 (ferroportin), a key protein responsible for exporting iron from cells, plays a vital role in maintaining systemic and cellular iron levels. In endometriosis, abnormalities in SLC40A1 expression or function may disrupt iron balance within the endometrial tissue, exacerbating oxidative stress through reactive oxygen species (ROS) production via Fenton reaction. This oxidative stress can impair endometrial stromal cell decidualization, a process crucial for embryo implantation, thereby contributing to compromised early pregnancy outcomes. Preliminary findings indicate reduced SLC40A1 expression in endometriosis patients, suggesting a link to elevated local iron levels and increased oxidative stress within the endometrium, which may disrupt normal decidualization processes essential for successful pregnancy. To further investigate these mechanisms, menstrual effluent derived stromal cells and organoid models will be employed to characterize how SLC40A1 influences iron dynamics, oxidative stress markers, and lipid peroxidation during decidualization. Complementing these studies, genetic manipulation of SLC40A1 in mouse models aims to provide deeper insights into its impact on reproductive outcomes, specifically its role in protecting against decidual ferroptosis—a form of cell death associated with excessive iron and lipid peroxidation. Additionally, the transcriptional regulation of SLC40A1 by FOXO1 and GATA2, critical transcription factors involved in oxidative stress response and decidualization, will be explored through genome wide (CUT&RUN) analyses and luciferase reporter assays. These experiments aim to elucidate the direct interactions between FOXO1/GATA2 and the regulatory regions of the SLC40A1 gene, revealing how these factors influence SLC40A1 expression and modulate cellular iron levels within the endometrium. Ultimately, uncovering iron dynamic and oxidative stress networks in endometriosis could uncover novel therapeutic targets for improving reproductive health outcomes. By integrating clinical samples with mechanistic insights from cellular and animal models, this research aims to develop targeted interventions addressing endometriosis-associated infertility and pregnancy complications. The F32 grant will not only provide the necessary financial support for my research but also offer valuable career development opportunities. This includes professional training, mentorship, and the chance to build a network with leading experts in the field.