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.33-35(Table 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.