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.