6.2 GDM
GDM is one of the most prevalent metabolic problems of pregnancy,
associated with abnormal placental functioning.97, 98A recent study found that greater blood ferritin levels, which in turn
enhance the oxidative stress, can be caused by higher pre-pregnancy BMI.
In GDM patients, ferritin and oxidative stress can raise blood sugar
levels, possibly via causing pancreatic beta-cell ferroptosis in
vivo.99
Additionally, the diabetes placenta typically exhibits abnormal
trophoblast proliferation, autophagy, and cell cycle regulation, which
promotes the progression of GDM.100-102 High glucose
concentration induces trophoblasts to produce an excessive amount of
ROS, which may starts the pathogenesis of GDM.103, 104Moreover, in trophoblastic cells of GMD patients, high glucose exposure
causes an increase in SIRT3 protein level, iron buildup, and lipid
peroxidation. Eventually, this causes ferroptosis.105It is worth noting that in GDM, abnormalities in lipid metabolism, which
is a key factor in ferroptosis, occur in addition to glucose metabolism.
Adiponectin, a lipid metabolism regulator, can reduce placental injury
in GDM by restoring CPT-1 activity to inhibit
ferroptosis.80
Ferroptosis and OC
OC is one of the most fatal malignant tumors with a five-year relative
survival below 50%.106, 107 Mounting evidence have
been revealed that ferroptosis has a closely relationship with OC,
although the potent therapeutic strategies and the pathogenesis of OC
have yet to been fully uncovered. Accumulation of iron promotes the
development of OC. Iron excess intracellular iron and an increased
reliance on iron for proliferation are typical features of high-grade
ovarian cancer. A forced reduction in intracellular iron inhibits tumor
growth as well as tumor cell intraperitoneal
dissemination.108 Therefore, the drugs which can
reduce intracellular iron, such as binding iron chelators and cytotoxic
drugs to TfR1 are effective on the treatment of OC.108
Moreover, ferroptosis provides a new solution for the problems of drugs
resistance in OC. For example, erastin, a ferroptosis reducer, was
proved to inhibit System Xc- and result in depletion of
GSH.109 According to a study, erastin and cisplatin
jointly limit the proliferation of OC cells, which may be affected by a
ROS-mediated mechanism that improves cisplatin therapy. This suggests a
unique method for overcoming cisplatin therapy
resistance.110 Since the role of ferroptosis in
ovarian cancer has been reviewed in previous reviews, this article will
not repeat it again. However, the ability of ferroptosis inducers to
kill tumor cells in vitro has been demonstrated, but in experimental
animal models using immunocompromised mice, they have not been
particularly successful. Fortunately, a recent study showed that
ferroptosis promotes iron death in PMN MDSCs in the tumor
microenvironment as a distinct and specific immunosuppressive
mechanism.111 Overall, ferroptosis is an effective
target for tumor treatment according to the current researches.
C onclusion
and perspective
An aberrant humoral microenvironment, iron overload, excessive ROS,
causes normal female reproductive cells such as GCs and trophoblasts, to
ferroptosis. This causes the ovary, placenta, and embryo to become
dysfunctional, which ultimately results in a number of illnesses
associated to reproduction. Ferroptosis connects iron, amino acids,
lipids, and redox chemistry into a single, coherent network. Today, it
is understood that this network plays a role in a wide range of
biological activities in the female reproductive system, including both
normal physiology and various diseases. As more information is revealed
about the intricate regulatory mechanism and consequences of ferroptosis
that controls various diseases, the field will undoubtedly become more
and more exciting.
We realize that there are still some challenges in the research of
ferroptosis in female reproductive system related diseases. Firstly, it
is worth to note that several studies have simply demonstrated the
coexistence of ferroptosis and a pathological state of sickness or the
special vivo microenvironment of patients which tends to promote
ferroptosis in reproductive function related cells, such as GCs,
Trophoblasts. We yet not to know the direct molecular events are
responsible for the eventual pathological changes of these diseases and
this will be a hotspot in future research.
Furthermore, ferroptosis plays a crucial role in the treatment of
illnesses of the female reproductive system. However, more attention
should be attached on that ferroptosis may play a dual role in some
disease such as EMs. Furthermore, we cannot ignore that ferroptosis
occurs throughout normal physiological processes and is crucial for the
normal development of tissues and organs. Thus, one area of future
research will focus on tailored ferroptosis therapy for various tissues.
Exosomes have gained increasing notoriety recently as highly effective
targeted drug delivery systems in tumor therapy. Targeting and
biocompatibility of preparations based on ferroptosis-related exosomes
may offer a cutting-edge and potent delivery platform for the treatment
of anti-reproductive disorders. In addition, there are numerous factors
that have been found to cause and prevent ferroptosis, but it is unknown
whether one can be the optimal therapeutic index, be employed in both
patients and animal models, and be chemically managed.
Of note, A new type of death known as ”Cuproptosis” is induced by an
overabundance of copper. Interestingly, ferroptosis and cuproptsis,
these two distinct types of cell death, both closely associated with
mitochondria. It must be exciting to find out whether there is any
connection between these two pathways that might be significant and lead
to further treatment possibilities for female reproductive diseases.
In summary, there is a wealth of foreseeable opportunities to elucidate
both the and the effects and execution mechanisms of ferroptosis in
female reproduction. Such studies will not only provide new targets for
the therapy for diseases but also provide new ideas for illuminating the
breadth of physiological and pathological roles of ferroptosis in other
disease linked with iron overload and oxidant stress.