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.