6.1.2 The mechanism of ferroptosis in PE
Hepc is an iron metabolism regulator. Hepc inhibits iron ion transport by binding to the membrane iron transporter (FPN) on the basolateral surface of intestinal epithelial cells and the plasma membrane of reticuloendothelial cells (macrophages). Finally, Hepc degrades the transporters in lysosomes, inhibits FPN, and prevents the output of iron ions from cells. Its levels have been observed to decrease in PE patients in some research 85, while being raised during pregnancy in other studies.86 According to reports, the occurrence of PE and early pregnancy’s high serum hepc level.86 The study on the change in hepc level in PE patients is still debatable at this time, and more research is required to understand its mechanism. In PE, free iron, ferritin, and transferrin saturation levels rise in contrast to normal pregnancy, but transferrin receptor levels fall.87-89 Additionally, the mother’s plasma blood volume increases during pregnancy, this has little impact on pregnancy-related issues. However, the increased plasma volume has the ability to change other parameters, such as the iron concentration, which have differing impacts on pregnancies with normal and PE.90
In addition, in the PE model, mir-30b-5p can inhibit the cys2 / glutamate reverse transporter and Pax3, which decreases the expression of transferrin 1, increasing the amount of unstable Fe2 + and encouraging ferroptosis in PE patients.79 In addition, the expression of mir-210 in placenta has been found increased, leading to iron accumulation and autophagosome formation in trophoblasts, as well as hemosiderin deposition in placental stromal trophoblasts.91Therefore, mounting evidence demonstrated iron overload in PE can lead to ferroptosis, especially in trophoblasts which are sensitive to ferroptosis due to the high expression of two ferroptosis- inducer genes Sat1, Lpcat3,53 and further lead to placental dysfunction and trophoblast damage.
Studies have revealed that patients with PE and eclampsia had considerably higher serum levels of MDA, an oxidation byproduct that probably leads to ferroptosis.92-94 Moreover, it has been discovered that PE’s hypoxia activates the nuclear factor erythroid-2-related factor 2 (Nrf2), a key antioxidant regulator. It can relieve the symptoms of PE by the activation of the Nrf2/HO-1 signaling pathway and the expression of SLC7A11, GPX4, and FPN1 to inhibit oxidation stress and ferroptosis.95 In addition, DJ-1, essential for activating and stabilizing Nrf2 to carry out further function, has also been found elevated to play a protective role in PE.96 Currently, the primary focus of PE treatment is a placental hypoxia cure. Although various PE-related parameters have been linked to placental oxidative stress, it is unclear how these factors specifically affect ferroptosis regulation.