Double-edged roles of ferroptosis in endometriosis and endometriosis-related infertility

Li Y, Yangshuo Li, Yalun He, He Y, Cheng W, Wen Cheng, Zhihao Zhou, Ni Z, Zhexin Ni, Chaoqin Yu
Cell death discovery · 2023 · vol. 9(1) , pp. 306 · doi:10.1038/s41420-023-01606-8 · PMID:37607902 · PMC10444804 · W4386055321
Review OA: gold CC0 ⤵ 18 in-corpus citations
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This review explores ferroptosis's dual roles in endometriosis, detailing how iron overload contributes to ovarian cell and embryo damage, thereby causing infertility.

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This 2023 review paper examines how ferroptosis—a regulated, iron-dependent cell death driven by lipid peroxidation—may contribute to endometriosis and endometriosis-related infertility, focusing on evidence of elevated iron in ectopic lesions, peritoneal fluid, and follicular fluid and summarizing proposed ferroptosis regulatory pathways. The authors synthesize findings that ferroptosis can damage ovarian granulosa cells, oocytes, and embryos, and they propose a “threshold” model in which ectopic tissue may resist ferroptosis yet also undergo partial ferroptotic death that could promote downstream proliferative signaling via cytokines. A major caveat the paper flags is that the specific mechanisms linking iron overload to ferroptosis execution and the metabolic “checkpoints” that shift ferroptosis thresholds in endometriosis remain unclear and require further exploration. This paper is centrally about endometriosis — it reviews ferroptosis mechanisms in endometriosis and how they may underlie endometriosis-related infertility.

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Abstract

Endometriosis is strongly associated with infertility. Several mechanisms have been reported in an attempt to elucidate the pathophysiological effects that lead to reduced fertility in women with endometriosis. However, the mechanisms by which endometriosis affects fertility have not been fully elucidated. Ferroptosis is a novel form of nonapoptotic cell death that is characterized by iron-dependent lipid peroxidation membrane damage. In past reports, elevated iron levels in ectopic lesions, peritoneal fluid and follicular fluid have been reported in patients with endometriosis. The high-iron environment is closely associated with ferroptosis, which appears to exhibit a double-edged effect on endometriosis. Ferroptosis can cause damage to ovarian granulosa cells, oocytes, and embryos, leading to endometriosis-related infertility. This article summarizes the main pathways and regulatory mechanisms of ferroptosis and explores the possible mechanisms of the formation of an iron-overloaded environment in endometriotic ectopic lesions, peritoneal fluid and follicular fluid. Finally, we reviewed recent studies on the main and potential mechanisms of ferroptosis in endometriosis and endometriosis-related infertility.
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How does endometriosis tolerate the high levels of iron in the peritoneal fluid? Could ferroptosis inducers be the next potential treatment for endometriosis? How do iron overload and ferroptosis affect endometriosis-related infertility? How can ferroptosis be balanced to treat endometriosis and endometriosis-related infertility? How does endometriosis tolerate the high levels of iron in the peritoneal fluid? Could ferroptosis inducers be the next potential treatment for endometriosis? How do iron overload and ferroptosis affect endometriosis-related infertility? How can ferroptosis be balanced to treat endometriosis and endometriosis-related infertility?

Facts

There is a high iron level in both peritoneal and follicular fluid in patients with endometriosis. A high-iron environment may be key to triggering ferroptosis. Ferroptosis may have a double-edged effect on the development of endometriosis. Ferroptosis impairs the function of oocytes and granulosa cells in patients with endometriosis. There is a high iron level in both peritoneal and follicular fluid in patients with endometriosis. A high-iron environment may be key to triggering ferroptosis. Ferroptosis may have a double-edged effect on the development of endometriosis. Ferroptosis impairs the function of oocytes and granulosa cells in patients with endometriosis.

Conclusion

In recent years, researchers have gradually appreciated and revealed the potential role of ferroptosis in endometriosis. These findings highlight the ability of ectopic endometrial tissue to resist iron overload-induced ferroptosis and promote ectopic lesion growth by mediating local cellular ferroptosis in peritoneal fluid in patients with endometriosis. However, oocytes from patients with endometriosis-related infertility are threatened by iron overload, and the development and maturation of oocytes are affected and prone to trigger cellular ferroptosis. This is possibly due to the immature antioxidant system and membrane repair mechanisms of the oocyte. Furthermore, although iron accumulation and lipid peroxidation are unique intermediate events in the onset of ferroptosis, they are not the ultimate executors. Lipid peroxidation can also occur in other cell death types, which depend on different ultimate effectors. Key regulators of ferroptosis can also regulate other types of cell death. For example, GPX4, a key factor in the antioxidant system, also inhibits apoptosis and necroptosis to protect cells from various insults [ 129 , 130 ]. Therefore, unique markers of ferroptosis in ectopic endometrial tissue require further identification. Currently, the detailed regulatory mechanisms of ferroptosis in endometriosis have not been fully elucidated. In conclusion, ferroptosis and its role in endometriosis, as well as endometriosis-related infertility, require systematic and in-depth studies.

Macrophage

Ferroptosis releases DAMPs and lipid oxidation products, which affect nonleukocytes and cause inflammatory cell death. However, it also mediates immune cell death that leads to losses of immune function, such as macrophage function. Macrophages phagocytose aged erythrocytes and process iron from erythrocytes to participate in iron metabolism. Excessive erythrophagocytosis leads to iron overload in macrophages and induces iron-dependent ferroptosis. Iron overload in bone marrow-derived macrophages can upregulate SLC7A11 expression via the ROS-NRF2-antioxidant response element (ARE) axis to reduce cellular sensitivity to ferroptosis [ 112 ]. In contrast, mice with GPX4-deficient bone marrow macrophages are susceptible to cell death caused by polymicrobial infection [ 113 ]. Furthermore, the release of DAMPs mediated by ferroptosis can affect macrophage polarization, and polarization imbalance can lead to various diseases or inflammatory conditions. For example, Kras G12D released from autophagy-dependent ferroptotic cancer cell death can limit the antitumour effects of macrophages by activating STAT3-mediated AGER-dependent M2 macrophage polarization [ 114 ]. Similarly, ferroptosis-mediated cell death that results in the release of 8-hydroxylamine (8-OHG) activates the STING1-dependent inflammatory pathway in surrounding macrophages and promotes M2 polarization [ 115 ]. Thus, ferroptosis directly impairs macrophages through the release of DAMPs. Macrophages play an indispensable role in the chronic inflammatory disease mechanism of endometriosis. Previous studies have shown that macrophages allow the growth of ectopic endometrial tissue, promote angiogenesis, and recruit nerve fibres to contribute to chronic pain [ 101 ]. In the human peritoneal cavity, macrophages consist of 50% leucocytes [ 116 ]. Unlike other cells that acquire Fe 2+ through TfRC and DMT1, the major source of iron for macrophages is through the disposal of haem-derived iron. Although macrophages have a remarkable ability to tolerate iron overload [ 117 ], the antioxidant capacity of macrophages is insufficient to cope with iron overload in this setting. This ultimately leads to the outcome of ferroptosis due to excessive phagocytosis of erythrocytes and ferritinophagy [ 118 ]. Activated M1 macrophages are more sensitive to ferroptosis than M2 macrophages, and this difference is associated with inducible nitric oxide synthase in M1 macrophages [ 119 ]. Therefore, iron overload in the peritoneal fluid may promote M2 macrophage polarization, inhibit the M1 macrophage phenotype and induce a subset of macrophage ferroptosis. Recent findings suggest that the M2 macrophage phenotypes with tissue repair effects predominate in the peritoneal fluid in women with endometriosis [ 120 ]. Therefore, the peritoneal environment possibly promotes ectopic endometrial tissue proliferation and growth by influencing macrophage M2 polarization via iron overload, which releases anti-inflammatory cytokines, growth factors, and other reparative components [ 121 ]. In summary, the intrinsic association between macrophages and endometriosis is much less well-studied than that for other diseases, such as cancer. The mechanisms by which macrophages resist ferroptosis help provide us with new insights into the mechanisms of ferroptosis in the endometriosis model.

Ferroptosis

The iron-overloaded environment induced by retrograde menstruation is suspected to be an important factor in inducing the continued proliferation of ectopic endometrial tissue. In addition, ferroptosis promoted by an iron-overloaded environment appears to be detrimental to oocytes or embryos and is also closely related to endometriosis-related infertility. Peritoneal fluid and follicular fluid are the external microenvironments for oocyte maturation and blastocyst formation, and these abnormal microenvironments affected by iron overload may lead to impaired reproductive function.In recent years, studies on the role and mechanism of iron overload and ferroptosis in endometriosis-related infertility have been reported successively (Table 1 ). Table 1 Studies on the association of iron overload and ferroptosis with endometriosis-related infertility. Author, date (Ref.) Model Research content Main results Final outcomes Chen et al., 2021 [ 104 ] In vivo: C57BL/6J female mice In vitro: mouse two-cell stage embryos Iron overload in endometriosis peritoneal fluid Disrupted mitochondrial function, decreased ATP levels, increased ROS levels, hyperpolarized MMP, triggered apoptosis and ferroptosis Compromised preimplantation mouse embryo development Li et al., 2021 [ 16 ] In vivo: C57BL/6J female mice In vitro: mouse two-cell stage embryos Iron overload in endometriosis peritoneal fluid Disrupted blastocyst formation, decreased GPX4 expression, disrupted mitochondrial function, decreased ATP levels, increased ROS levels and hyperpolarized MMP, upregulated HMOX1 Embryotoxicity and early embryo ferroptosis Ni et al., 2022 [ 110 ] In vivo: Kunming female mice In vitro: mouse granulosa cells and human granulosa cells Iron overload in endometriosis follicular fluid Decreased GPX4 and GSH expression, increased NCOA4 expression, NCOA4-mediated ferritinophagy, released exosomes of granulosa cell containing abnormal miRNAs Ferroptosis of granulosa cells and oocyte dysmaturity Li et al., 2020 [ 109 ] In vitro: mouse oocytes Transferrin insufficiency and iron overload in endometriosis follicular fluid Reduced concentration of transferrin with three analogues, increased concentration of ferricion, decreased maturation in vitro rate of mouse oocytes Oocyte dysmaturity Hu et al., 2021 [ 111 ] In vitro: porcine oocytes Iron overload-induced ferroptosis in porcine oocytes Increased intracellular ROS generation, decreased intracellular free thiol levels, induced mitochondrial dysfunction, triggered autophagy, decreased embryonic developmental potential Impaired oocyte meiosis, decreased oocyte quality and embryonic developmental competence Ding et al., 2022 [ 112 ] In vivo: C57BL/6J female mice Iron overload in endometriosis ovarian function Increased MDA levels, decreased GPX4 and GSH expression, decreased growing follicles numbers Cellular ferroptosis, compromised ovarian function Studies on the association of iron overload and ferroptosis with endometriosis-related infertility. In vivo: C57BL/6J female mice In vitro: mouse two-cell stage embryos In vivo: C57BL/6J female mice In vitro: mouse two-cell stage embryos In vivo: Kunming female mice In vitro: mouse granulosa cells and human granulosa cells Iron overload in peritoneal fluid can affect embryonic development by leading to embryo toxicity and ferroptosis. Chen et al. showed that the pelvic iron-overloaded environment in patients with endometriosis impaired early embryonic development and caused embryo toxicity by triggering GPX4 downregulation-dependent ferroptosis in preimplantation mouse embryos. This leads to endometriosis-related infertility and adverse pregnancy outcomes [ 122 ]. During this process, excess iron could induce the excessive accumulation of ROS, which leads to oxidative stress and damages mitochondrial function in preimplantation mouse embryos. This triggers ATP generation impairment and decreases mitochondrial membrane potential (MMP) levels. Moreover, the expression of GPX4 in embryos was significantly decreased [ 122 ]. GPX4 is essential for embryonic development. GPX4 deficiency results in abnormal embryonic development compared to the deficiencies of all other GPX family members and ultimately produces lethal phenotypes in mice [ 123 ]. In addition to disrupting mitochondrial function, the iron-overload environment in the peritoneal fluid of endometriosis could also reduce the expression of GPX4 and induce lipid peroxidation. Thus, blastocyst formation is disrupted, and embryo toxicity and ferroptosis occur. The ferroptosis inhibitor Fer-1 could improve these adverse conditions [ 16 ]. In addition, haem oxygenase 1 (HMOX1) is upregulated in embryonic ferroptosis, and inhibition of HMOX1 can maintain normal mitochondrial function, thereby preventing ferroptosis from occurring [ 16 ]. Thus, HMOX1 may play an important role in mediating embryo ferroptosis. Its overexpression can play a pro-oxidative role and induce ferroptosis by increasing Fe accumulation and lipid peroxidation [ 124 , 125 ]. The total iron levels and ferritin and TfR1 expression levels in endometrioma-proximal follicles are higher than those in endometrioma-distal follicles and healthy ovarian follicles. Moreover, the oocyte retrieval rates in endometrioma-proximal and -distal follicles are lower than those in healthy ovarian follicles [ 126 ]; this illustrates that excessive iron intake by follicles leads to cytotoxic accumulation that affects normal oocyte development. In recent research, Li et al. studied specific proteins at different concentrations in the follicular fluid of patients with advanced endometriosis and found that the transferrin concentration of the three analogues of cDNA FLJ53691, cDNA FLJ54111, and TRF variant Fragment in the follicular fluid decreased. The iron ion concentration of these analogues increased. The environment of transferrin deficiency and iron overload could increase the level of ROS and lead to oxidative stress. Thus, the in vitro maturation rate of mouse oocytes could significantly decrease, which might be one of the causes of endometriosis-related infertility [ 89 ]. Ni et al. found that iron-overloaded follicular fluid could trigger ferroptosis in granulosa cells and immaturity of oocytes, thereby increasing the risk of endometriosis-related infertility [ 90 ]. The iron-overloaded environment of follicular fluid could not only inhibit the expression of GPX4 and its upstream regulatory target GSH but also cause the high expression of NCOA4 in granulosa cells. This would lead to NCOA4-dependent ferritinophagy, which increases lipid peroxidation in granulosa cells and promotes ferroptosis. Moreover, granulosa cells undergoing ferroptosis cannot exert nutritional and paracrine functions on oocytes and can release granulosa cell exosomes containing abnormal miRNAs. Therefore, oocyte maturation is inhibited, and endometriosis-related infertility can develop. The iron chelators deferoxamine mesylate and VITE could change these circumstances by increasing GPX4 expression and decreasing iron overload [ 90 ]. Furthermore, after in vitro ferroptosis inducer ferric ammonium citrate (FAC) intervention, mammalian oocytes experienced increases in ROS and autophagy-related protein LC3 and mitochondrial dysfunction. Additionally, there was significant accumulation of Fe 2+ in the cytoplasm and decreases in the polar body (PB) expulsion rate and blastocyst formation rate. Thus, exogenous ferroptosis inducer-induced ferroptosis inhibits oocyte meiosis by increasing oxidative stress, inducing mitochondrial dysfunction, triggering autophagy splitting process and affecting oocyte quality [ 127 ]. Conversely, the inhibition of ferroptosis might not only inhibit the progression of endometriosis, but also improve the adverse effects of iron overload on ovarian function, thereby improving fertility and becoming a therapeutic approach for endometriosis-related infertility [ 128 ]. In summary, these findings suggest that iron overload and its induced ferroptosis in peritoneal fluid and follicular fluid in patients with endometriosis play an important role in the progression of endometriosis-related infertility (Fig. 4 ). Therefore, mitigating the impact of iron stress on the local microenvironment, such as the use of antioxidant agents or iron chelators, is expected to be an effective approach for the prevention and treatment of endometriosis-related infertility. Fig. 4 Oocyte and granulosa cells in iron-overloaded follicular fluid in endometriosis. Iron-overloaded follicular fluid in endometriosis plays an important role in the progression of endometriosis-related infertility. Iron overload in peritoneal fluid affects the mitochondrial function of oocytes and decreases GPX4 expression, thereby inducing ferroptosis and toxicity by promoting lipid peroxidation. Moreover, iron overload in follicular fluid not only decreases GPX4 and GSH expression, but also increases NCOA4 expression and mediates ferritinophagy. Thus, granulosa cell ferroptosis is induced by promoting lipid peroxidation. Granulosa cells undergoing ferroptosis cause oocyte dysmaturity by releasing exosomes containing abnormal miRNAs. These situations can contribute to endometriosis-related infertility. Created with BioRender.com. Iron-overloaded follicular fluid in endometriosis plays an important role in the progression of endometriosis-related infertility. Iron overload in peritoneal fluid affects the mitochondrial function of oocytes and decreases GPX4 expression, thereby inducing ferroptosis and toxicity by promoting lipid peroxidation. Moreover, iron overload in follicular fluid not only decreases GPX4 and GSH expression, but also increases NCOA4 expression and mediates ferritinophagy. Thus, granulosa cell ferroptosis is induced by promoting lipid peroxidation. Granulosa cells undergoing ferroptosis cause oocyte dysmaturity by releasing exosomes containing abnormal miRNAs. These situations can contribute to endometriosis-related infertility. Created with BioRender.com.

Introduction

Endometriosis refers to an oestrogen-dependent inflammatory disease characterized by the seeding and growth of endometrial tissue outside the uterine cavity [ 1 ]. These endometrial tissues can be seeded on the peritoneal cavity, ovaries, and fallopian tubes, as well as distant tissues and organs [ 2 ]. The simultaneous detection of endometrial stromal and glandular components in histological biopsies is necessary to ascertain endometriosis [ 3 ]. The common clinical symptoms of endometriosis include chronic pelvic pain and infertility, which severely affect the physical and mental health of patients [ 4 ]. A total of 25 to 50% of women with infertility are clinically treated for endometriosis, and 30 to 50% of women with endometriosis suffer from infertility [ 5 , 6 ]. However, the exact link between endometriosis and infertility is unknown, and many factors may be involved in this link. For example, mechanical disruption by pelvic adhesions in women with advanced endometriosis affects oocyte release and transport, decreases sperm motility, and impairs zygote implantation, which leads to reduced fertility [ 7 ]. However, the causes of infertility in women with mild endometriosis remain unclear and are subject to numerous speculations, mainly relating to endocrine abnormalities, immune disorders, oxidative stress, and aberrant gene expression [ 8 , 9 ]. Ferroptosis is a novel form of regulated cell death that is distinct from accidental cell death; it can be mediated by different molecular signalling pathways [ 10 , 11 ]. Specifically, ferroptosis is defined as an iron-dependent regulated form of necrosis that is caused by massive lipid peroxidation-mediated membrane damage, and this regulated necrosis plays a crucial role in the development and disease of various organisms [ 12 , 13 ]. Although many open questions remain in ferroptosis research, numerous reports have stated that ferroptosis is closely related to many diseases, such as cancer, ischaemic organ injury, and degenerative diseases [ 14 ]. In several recent reports, ferroptosis was detected in ectopic endometrial tissue in endometriosis characterized by periodic haemorrhage [ 15 ] and in the early embryo in iron-overloaded peritoneal fluid [ 16 ]. However, the specific role and mechanism of ferroptosis in endometriosis, as well as in endometriotic infertility, remain unclear. In this article, we explored the possible mechanisms of the formation of an iron-overloaded environment in endometriotic ectopic lesions, peritoneal fluid and follicular fluid. In addition, we summarized the main pathways and regulatory mechanisms of ferroptosis and discussed its involvement in endometriosis and endometriosis-related infertility to provide new insights into the discovery of novel therapeutic targets. We propose the notion that a threshold exists for the occurrence of ferroptosis in ectopic endometrial tissue in endometriosis. Once beyond the threshold, iron overload and oxidative damage can lead to ferroptotic cell death. Multiple oxidative and antioxidant systems can be activated simultaneously and operate in parallel to adjust this threshold, which is implicated in the metabolic reprogramming of the affected cells [ 17 ]. On the one hand, ectopic endometrial tissues in patients with endometriosis present resistance to ferroptosis, probably because of the shared antioxidant system in macrophages and ectopic lesion cells in the peritoneal fluid. On the other hand, ectopic endometrial tissue is partially subjected to ferroptosis, which seems beneficial. However, this process is followed by the activation of a series of downstream signalling pathways and the release of cytokines that promote cell proliferation. Thus, ectopic endometrial tissue might shift the threshold at which ferroptosis occurs by metabolic reprogramming towards a proliferative advantage for itself, something that seems to be similar to that of cancer cells. However, the specific metabolic checkpoints of the altered thresholds need further exploration, which is a future research direction.

Iron Overloaded

Endometriosis can be divided into three phenotypes due to the diverse of underlying aetiologies: superficial peritoneal endometriosis, ovarian endometriosis, and deep infiltrating endometriosis [ 82 ]. Studies have shown that the levels of iron, ferritin, and haemoglobin are higher in the peritoneal fluid of women with endometriosis than in that of normal women [ 83 ]. Moreover, iron aggregates are present in endometriotic lesions of women with endometriosis and model mice [ 84 , 85 ]. In addition, ovarian endometriomas contain high amounts of free iron, and the surrounding follicles nearby are also iron overloaded, which adversely affects oocyte development and quality [ 86 ]. However, the original cause of the iron-overloaded environment in ectopic lesions, peritoneal fluid, and follicular fluid of endometriosis is still unknown and may be related to the excessive degradation of red blood cells and increased influx caused by menstrual reflux and repeated bleeding of local lesions [ 87 ]. Retrograde menstruation and ectopic endometrial bleeding lesions can transport menstrual endometrial tissue and red blood cells to the peritoneal cavity. Some of these tissues and cells will be phagocytized, absorbed, and degraded by peritoneal macrophages and stored in the form of haemosiderin. Additionally, ferritin and haemoglobin are released into the peritoneal fluid [ 83 ]. The haem released by the hydrolytic digestion of haemoglobin is catabolized by haem oxygenase to generate active iron and forms iron-ferritin deposition. This overwhelms the iron homoeostasis and iron clearance system, finally leading to an iron-overloaded environment in peritoneal fluid and ectopic lesions of endometriosis [ 88 ]. In the environment of intraperitoneal iron overload, excess iron is transported by peripheral TF to cells within the ovary. This iron can bind to TfR1 on the surface of cells and trigger endocytosis [ 89 ]. In addition, menstrual reflux to the ovary and repeated bleeding in local lesions of the ovary may also lead to an iron-overloaded environment in follicular fluid. Excessive accumulation of intraperitoneal iron can lead to the overproduction of ROS and the enhanced activation of nuclear factor-kappaB (NF-κB). This enhances the migration ability of human endometriotic cells by promoting the expression of matrix metalloproteinases (MMPs), aggravating inflammation, angiogenesis, and cell adhesion to participate in the progression of endometriosis lesions [ 59 ]. Moreover, iron overload in follicular fluid can cause granulosa cell death and affect oocyte maturation and quality, ultimately increasing the risk of endometriosis-related infertility [ 89 , 90 ].

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