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.

铁过载与妊娠并发症有关。铁转运蛋白（FPN）是哺乳动物细胞中唯一已知的铁输出蛋白。我们假设 FPN 在铁死亡（一种铁依赖性非凋亡性程序性细胞死亡过程）中具有重要的功能，并且可能在妊娠成功中发挥关键作用。我们通过免疫组织化学研究了从患有/不患有先兆子痫 (PE) 和自发性早产 (SPTB) 的妊娠中收集的组织中 FPN 在胎盘/胎膜中的表达。FPN 在胎盘/胎膜中的滋养细胞和蜕膜细胞中高度表达。与健康妊娠相比，SPTB 胎膜染色显着减少（P  = 0.046）。使用 1 μM 醋酸甲羟孕酮和 0.5 mM 二丁酰-cAMP 进行体外蜕膜化诱导后，永生化人子宫内膜基质细胞 (HESC) 中的 FPN 表达增加。此外，FPN 敲低的 HESC 细胞和永生化绒毛外滋养层 SW71 细胞均显示出对铁死亡诱导剂erastin 的显着敏感性（分别为P  < 0.001 和P  = 0.009）。HESC 和 SW71 细胞的存活并未因培养基中添加柠檬酸铁铵的铁而受到负面影响。然而，在非致死剂量的erastin存在下，SW71细胞比HESC细胞对生理铁更敏感（P  <0.001）。总而言之，我们的数据表明，FPN 敲低的 HESC 和 SW71 细胞对erastin 的敏感性增加，并且滋养层细胞在铁死亡应激下对铁过载的敏感性增加，支持 FPN 可以防止妊娠期间铁死亡的假设。