Ferroportin expression and regulation in human placenta/fetal membranes: Implications for ferroptosis and adverse pregnancy outcomes

Iron overload is associated with pregnancy complications. Ferroportin (FPN) is the only known iron exporter in mammalian cells. We hypothesize that FPN is functionally important in ferrotopsis, a process of iron-dependent non-apoptotic programmed cell death, and may have a critical role to play in pregnancy success. We investigated the expression of FPN in placenta/fetal membranes by immunohistochemistry in tissues collected from pregnancies with/without preeclampsia (PE) and spontaneous preterm birth (SPTB). FPN was highly expressed in both trophoblasts and decidual cells found in placenta/fetal membranes. Staining was significantly reduced in fetal membranes from SPTB versus healthy pregnancies (P = 0.046). FPN expression in immortalized human endometrial stromal cells (HESC) increased with in vitro decidualization induction using 1 μM of medroxyprogesterone acetate and 0.5 mM of dibutyryl-cAMP. In addition, both HESC cells and immortalized extravillous trophoblast SW71 cells with FPN knockdown showed significant sensitivity to ferroptosis inducer, erastin (P < 0.001 and P = 0.009, respectively). The survival of both HESC and SW71 cells was not negatively affected by iron supplementation with ferric ammonium citrate in the medium. However, SW71 cells were more sensitive than HESC cells to physiologic iron in the presence of a non-lethal dose of erastin (P < 0.001). Taken together, our data demonstrating increased sensitivity of FPN knockdown HESC and SW71 cells to erastin and increased sensitivity of trophoblasts to iron overload under ferroptotic stress support the hypothesis that FPN protects against ferroptosis during pregnancy.