Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss

Iron is necessary for various critical biological processes, but iron overload is also dangerous since labile iron is redox-active and toxic. We found that low serum iron and decidual local iron deposition existed simultaneously in recurrent pregnancy loss (RPL) patients. Mice fed with a low-iron diet (LID) also showed iron deposition in the decidua and adverse pregnancy outcomes. Decreased ferroportin (cellular iron exporter) expression that inhibited the iron export from decidual stromal cells (DSCs) might be the reason for local iron deposition in DSCs from low-serum-iron RPL patients and LID-fed mice. Iron supplementation reduced iron deposition in the decidua of spontaneous abortion models and improved pregnancy outcomes. Local iron overload caused ferroptosis of DSCs by downregulating glutathione (GSH) and glutathione peroxidase 4 levels. Both GSH and cystine (for the synthesis of GSH) supplementation reduced iron-induced lipid reactive oxygen species (ROS) and cell death in DSCs. Ferroptosis inhibitor, cysteine, and GSH supplementation all effectively attenuated DSC ferroptosis and reversed embryo loss in the spontaneous abortion model and LPS-induced abortion model, making ferroptosis mitigation a potential therapeutic target for RPL patients. Further study that improves our understanding of low-serum-iron-induced DSC ferroptosis is needed to inform further clinical evaluations of the safety and efficacy of iron supplementation in women during pregnancy.

Automated summary

Iron is crucial for biological processes, but excessive iron can be toxic. In patients with recurrent pregnancy loss (RPL), low serum iron and iron deposition in the decidua were simultaneously observed. Mice fed with a low-iron diet also showed iron deposition in the decidua and adverse pregnancy outcomes. Decreased expression of ferroportin, an iron exporter, in decidual stromal cells (DSCs) may explain the local iron deposition. Iron supplementation reduced iron deposition and improved pregnancy outcomes. Excessive iron led to ferroptosis of DSCs, but supplementation of glutathione (GSH) and cystine reduced cell death. Ferroptosis inhibitors also attenuated DSC ferroptosis and reversed embryo loss, indicating a potential therapeutic target for RPL patients.