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.