5.1.1 The two sides effects of ferroptosis in EMs
On one hand, it is believed that ferroptosis is the process by which
endometrial cells dispersed during retrograde menstruation are expelled
from the peritoneal cavity. Additionally, a prior study found that
ectopic endometrial stromal cells (EESCs) were more susceptible to the
effects of erastin therapy than normal endometrial stromal cells
(NESCs), with the help of unique microenvironment and reduced
ferroportin expression.43 However, the endometrial
cells enable to survive, and implant in vivo of EMs
patients.44 It
seems that EESCs are resistant to ferroptosis displaying a general
tendency to block the ferroptosis gene pathway, according to the most
recent meta-analysis study.45 Endometriotic tissues
appear to be able to benefit from intracellular high iron loads for
energy metabolism and cell proliferation by the resistance to
ferroptosis while safeguarding themselves from the
ferroptosis.46-48
Several ferroptosis regulators are found to alter for getting rid of
ferroptosis (Figure 3). Ferritin can be transported to autophagosomes
by nuclear receptor coactivator 4 (NCOA4). and then fuse with lysosomes
to degrade ferritin into active iron.49 In
endometrium, it was found to be diminished. Additionally, it was
discovered that the ectopic endometrium had increased expression of FTL,
a crucial component of the iron ion storage protein.50These modifications enhance the insensitivity to ferroptosis and lower
the intracellular amounts of free iron ions.45
Interestingly, GSH is inhibited in ectopic
endometrium.51 The expression of the lncRNA
ADAMTS9-AS, on the other hand, was improved in the ectopic endometrium.
By sponging miR-6516-5p to increase the expression of GPX4, this
promoted ESCs to grow and migrate and prevented ectopic endometrium from
ferroptosis.52 In addition, repressing lipid oxidation
plays important role in ferroptosis-resistance in EMs. Through lower
expression of reticulocyte-type 15-lipooxygenase-1 (ALOX15) and spermine
N1-acetyltransferase 1(SAT1), coding for a crucial enzyme in polyamine
metabolism and also promotes p53-dependent
ferroptosis,53 lipid oxidation is hindered in eutopic
endometrial tissue of individuals with endometriosis. Of note, this
inhibition increased in ectopic endometrium, due to
ACSL5 and LPCAT3
downregulation.45
Moreover, Fibulin-1 (FBLN1), FBLN1 expression was enhanced in eutopic
and ectopic endometrial tissues with EMS, increasing ESC viability and
migration while decreasing ESC ferroptosis via enhancing the stability
of EFEMP1 protein.54 VDAC2 serving as the main pathway
for metabolite diffusion through the outer mitochondrial membrane and
crucial for intracellular redox response expression was significantly
downregulated in eutopic endometrium.55 Overall,
ferroptosis-resistance is a key contribute to the establishment and
maintain of EMs with complex regulatory pathways, and
ferroptosis-inducers may be a therapeutic option for it.
On the other hand, ferroptosis
contributes to the subsequent process of EMs, including infertility.
Study showed that some EECS that are undergoing ferroptosis have
paracrine effects that promote the development of new vascular systems
in the surrounding tissues, which may promote the growth of benign cells
and hasten the progression of this illness.56Furthermore, endometriosis, which causes uterine dysfunction and
interferes with embryo implantation, is closely associated with
infertility. Moreover, almost half of the infertility patients are
accompanied with EMs.57 Ferroptosis may contribute to
the infertility brought on by EMs.56 Follicle
dysplasia and decreased oocyte quality are the primary reasons of
infertility associated with EMs. It has been established that iron
overload is a common feature of the peritoneal fluid (PF) and follicular
fluid (FF) in EMs patients, causing ferroptosis, damaging oocytes and
embryos, and eventually leading to infertility.50, 58,
59
Oocyte maturation requires granulosa cells (GCs), the biggest cell group
and the primary functional cells in follicles. The normal development of
oocyte is reliant on the paracrine and nutritional activities of the
surrounding GCs.60 However, high levels of iron in FF
of EMs patients cause GCs to ferroptosis and produce exosomes after
ferroptosis, which further impair oocyte maturation.61Exosomes are extracellular vesicles that carry proteins, mRNAs, and
miRNAs to target cells.62 In a setting of iron
overload, granulosa cells’ exosomal miRNAs can control the expression of
several signal pathways, which ultimately reduces ovarian
reserve.61 Furthermore, ferroptosis is a reaction to
higher iron damage at the blastocyst stage, may cause to developmental
stoppage. Additionally, endometriosis PF’s iron excess prevents
blastocyst development and damages developing embryos by causing
ferroptosis and mitochondrial malfunction.59, 63 The
consequences of iron excess on embryo development have been the subject
of numerous studies, although the precise connection between ferroptosis
and embryotoxicity has not yet been established. According to a study,
HMOX1 is elevated during embryonic ferroptosis and inhibits it by
maintaining mitochondrial activity and protect them from oxidative
stress.63 When considered collectively, we cannot
ignore the impact of ferroptosis for the subsequent pathologic processes
of EMs.
In conclusion, endometriosis exists ferroptosis and
ferroptosis-resistance simultaneously. Ferroptosis-resistance is
essential for the form of endometriotic lesions, while ferroptosis plays
important role in the subsequent lesions. Recent studies have proposed
to promote ferroptosis in endometriotic lesions in order to treat EMs,
but iron overload microenvironment and ferroptosis impairing oocyte
function should be considered.64 Vitamin E and iron
chelators can significantly alleviate the symptoms of EMs-related
fertility, by increasing GPX4 and reducing iron
overload.61 Therefore, treatment methods related to
ferroptosis need to be considered comprehensively.