Abstract:
Ferroptosis, a cohering network integrating iron, amino acids, lipids, and redox chemicals together,is a unique regulated cell death (RCD). Iron overload, excessive reactive oxygen species (ROS), and lipid peroxidation all contribute to the onset of ferroptosis. In recent years, a growing body of evidence suggests that ferroptosis is associated with some female reproductive diseases. The purpose of our review is to give a brief description of ferroptosis activation mechanism and relationship to female reproductive diseases including infertility, pregnancy associated diseases and ovarian cancer.
Keywords: ferroptosis, regulated cell death, female reproductive diseases
Introduction
Recently, ferroptosis as one of regulated cell death (RCD) types was discovered and quickly emerged as a new area of focus for characterizing the pathophysiology and developing novel therapeutic and preventative strategies for associated illnesses.1 It is iron-dependent and visibly distinct from apoptosis, necroptosis, and pyroptosis.2-4 Numerous studies have demonstrated recently that ferroptosis has a role in the regulation of various disorders including tumorigenesis, ischemia–reperfusion injury, hematological diseases and reproductive diseases.5, 6In mice models of ischemia injury, ferrostatins and numerous other inhibitors of ferroptosis have been reported to perform a protective effect in the liver, kidney, brain, and heart.7-9
Reproductive diseases are common in female, and threaten large numbers of female health. Notably, mounting data suggests that ferroptosis is a key contributor to the ovarian and placental malfunction that underlies the majority of severe reproductive illnesses in recent years.10, 11 In this review, we have provided a comprehensive knowledge of ferroptosis and the connections between it and diseases of female reproductive system, including infertility, pregnancy associated diseases and ovarian cancer, such as endometriosis (EMS), polycystic ovarian syndrome (PCOS), primary ovarian insufficiency (POI), preeclampsia (PE) and gestational diabetes mellitus (GDM).
Ferroptosis and its activation mechanism
In contrast to other RCD, ferroptosis is an iron-dependent modality that produces deadly levels of lipid peroxidation to induce oxidative damage to cell membranes. Cells experiencing ferroptosis exhibit the morphological characteristics of packed and tightly packed mitochondria lacking cristae and intact plasma membrane, normal nuclei without the chromatin aggregation and display severe iron-dependent lipid peroxidation biochemically.2, 4, 12
Ferroptosis has a complicated activation mechanism. It is a comprehensive network with amounts of elements that can be divided into three aspects: imbalance iron level, GSH homeostasis and redox regulation, and excessive lipid peroxidation (Figure 1 ). Iron is a vital trace for the maintenance of life. One of the important cues to initiate membrane oxidation is the accumulation of free iron. The Fenton reaction takes place as free iron levels rise inside of cells, causing considerable amounts of ROS and lipid peroxidation as well as the breakdown of cell membrane structure and ferroptosis.2 Ferroptosis sensitive cells usually show higher transferrin receptor (TfR1) to increase iron intake while lower ferritin (FTHL1/FTL) to reduce iron storage, which eventually lead to iron overload and induce ferroptosis.13
GPX4, a powerful antioxidant, is required for the regulation of ferroptosis, which transforms hazardous lipid hydroperoxides to non-toxic ones.14 For GPX4 to function, glutathione production (GSH) is an essential cofactor. A cystine/glutamate antiporter called System XC- trades extracellular cystine (Cys2) required for GSH for intracellular glutamate. Of note, it consists of two subunits, SLC7A11 and SLC3A2. SLC7A11 is in charge of exchanging glutamate for cysteine, and SLC3A2 acts as a chaperone.15 Both the direct inhibition of GPX4 and the inhibition of GSH can lead to the accumulation of lipid peroxide in the cell membrane and the initiation of ferroptosis.
Additionally, polyunsaturated fatty acids (PUFAs) are a crucial component in the buildup of lipid peroxidation. Lysophosphatidylcholineacyl-transferase 3 (LPCAT3) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) are essential mediators of ferroptosis that are involved in the manufacture and modification of PUFA-phosphatidyl-ethanolamine phospholipids in cell membranes.16, 17 Large amounts of free lipid base are produced by PUFAs, which causes the cell membrane and plasma membrane to weaken, create protein holes, and lose their barrier function, disrupting intracellular homeostasis.2, 3, 18Furthermore, the decomposition products of lipid peroxidation activate a more serious cascade reaction and eventually lead to ferroptosis.4, 19
Other regulated cell deaths
Apart from ferroptosis, RCD also includes apoptosis, necroptosis, and pyroptosis, each of them with their own characteristics and functions from morphologically and biochemically. Caspase activation is a key component of apoptosis, which exhibits distinctive morphological characteristics such as cell shrinkage, nuclear fragmentation, chromosomal DNA fragmentation, and plasma-membrane blebbing.20-23 It is essential for preserving homeostasis and eliminating undesirable cells to prevent harming nearby cells throughout growth and aging.24 Moreover, it plays essential role for the smooth working of the female reproductive tract. Apoptosis resistance is present in a few reproductive tract malignancies. What’s more, it has been thought that apoptosis is a significant kind of cell death in oocyte loss.25, 26Necroptosis is activated by pro-inflammatory signal transduction as well as ischemic injury and viral infection displaying Plasma membrane rupture and cell enlargement. The activation and assembly of necrosome complexes containing receptor-interacting serine/threonine protein kinase 1 (RIPK1) and RIPK3 will lead to phosphorylation and oligomerization of MLKL, which will then lead to lipid peroxidation, cation influx, and ultimately cell death.27 It has been identified is effective for suppressing ovarian cancer growth.28, 29 Moreover, Induction of necroptosis in granulosa cell and oocyte may lead to follicular atresia.30 It also has been identified contribute to placental pathophysiology that underlies serious pregnancy complications such as PE and fetal growth restriction (FGR).31Pyroptosis, in contrast to other types of cell death, is brought on by pathogen invasion and is reliant on caspase activation. It is regarded as an inflammatory type of cell death that is brought on by intracellular sensors like NLRP3 that identify DAMPs, PAMPs, membrane disruptions, etc. It displays distinctive physical and morphological traits, such as chromatin condensation, intact nuclei, cellular enlargement, and plasma membrane rupture.32 It is a critical inflammatory pathway in the ovary and placenta linked with PE, PCOS, POI.33-35Table 1
Ferroptosis and female reproductive diseases
Ferroptosis has different effects on different diseases. In OC, ferroptosis is imperative for the treatment, but for PCOS, pregnancy diseases, like PE and GDM, is responsible for the occurrence of them. Interestingly, in EMS, ferroptosis-resistance seems to be responsible for the form of early ectopic lesion, while, ferroptosis is also an important contributor in subsequent disease progression. It is meaningful for illuminating a variety of ferroptosis pathways in female reproductive diseases, such as infertility, pregnancy illnesses, and ovarian cancer (Figure 2). Ferroptosis could be a therapeutic target for these diseases (Table 2).
Ferroptosis and infertility
Infertility affects between 8% and 12% of reproductive-aged couples worldwide.36 The pathology is not clear probably result from an immune system failure in the pelvic and uterine cavities, which affects ovulation, fallopian tube function, and endometrial receptivity, among other things. Notably, it is common to see that iron overload and oxidant stress microenvironment which have been found hinder preimplantation embryo development via ferroptosis in infertility patients. What’s more, many infertility-related diseases such as EMs, POI, and PCOS are found linked with ferroptosis.