{"paper_id":"a1fd0c2b-4d32-4935-b1f6-d6fa8bf721e4","body_text":"REVIEW ARTICLE OPEN\nDouble-edged roles of ferroptosis in endometriosis and\nendometriosis-related infertility\nYangshuo Li1,3, Yalun He 1,3, Wen Cheng 1,3, Zhihao Zhou 1, Zhexin Ni 1,2,4 ✉ and Chaoqin Yu 1,4 ✉\n© The Author(s) 2023\nEndometriosis is strongly associated with infertility. Several mechanisms have been reported in an attempt to elucidate the\npathophysiological effects that lead to reduced fertility in women with endometriosis. However, the mechanisms by which\nendometriosis affects fertility have not been fully elucidated. Ferroptosis is a novel form of nonapoptotic cell death that is\ncharacterized by iron-dependent lipid peroxidation membrane damage. In past reports, elevated iron levels in ectopic lesions,\nperitoneal fluid and follicular fluid have been reported in patients with endometriosis. The high-iron environment is closely\nassociated with ferroptosis, which appears to exhibit a double-edged effect on endometriosis. Ferroptosis can cause damage to\novarian granulosa cells, oocytes, and embryos, leading to endometriosis-related infertility. This article summarizes the main\npathways and regulatory mechanisms of ferroptosis and explores the possible mechanisms of the formation of an iron-overloaded\nenvironment in endometriotic ectopic lesions, peritoneal fluid and follicular fluid. Finally, we reviewed recent studies on the main\nand potential mechanisms of ferroptosis in endometriosis and endometriosis-related infertility.\nCell Death Discovery           (2023) 9:306 ; https://doi.org/10.1038/s41420-023-01606-8\nFACTS\n1. There is a high iron level in both peritoneal and follicular\nfluid in patients with endometriosis.\n2. A high-iron environment may be key to triggering ferroptosis.\n3. Ferroptosis may have a double-edged effect on the\ndevelopment of endometriosis.\n4. Ferroptosis impairs the function of oocytes and granulosa\ncells in patients with endometriosis.\nOPEN QUESTIONS\n1. How does endometriosis tolerate the high levels of iron in\nthe peritoneal fluid?\n2. Could ferroptosis inducers be the next potential treatment\nfor endometriosis?\n3. How do iron overload and ferroptosis affect endometriosis-\nrelated infertility?\n4. How can ferroptosis be balanced to treat endometriosis and\nendometriosis-related infertility?\nINTRODUCTION\nEndometriosis refers to an oestrogen-dependent in flammatory\ndisease characterized by the seeding and growth of endometrial\ntissue outside the uterine cavity [ 1]. These endometrial tissues can\nbe seeded on the peritoneal cavity, ovaries, and fallopian tubes, as\nwell as distant tissues and organs [ 2]. The simultaneous detection\nof endometrial stromal and glandular components in histological\nbiopsies is necessary to ascertain endometriosis [ 3]. The common\nclinical symptoms of endometriosis include chronic pelvic pain\nand infertility, which severely affect the physical and mental\nhealth of patients [ 4]. A total of 25 to 50% of women with\ninfertility are clinically treated for endometriosis, and 30 to 50% of\nwomen with endometriosis suffer from infertility [ 5, 6]. However,\nthe exact link between endometriosis and infertility is unknown,\nand many factors may be involved in this link. For example,\nmechanical disruption by pelvic adhesions in women with\nadvanced endometriosis affects oocyte release and transport,\ndecreases sperm motility, and impairs zygote implantation, which\nleads to reduced fertility [ 7]. However, the causes of infertility in\nwomen with mild endometriosis remain unclear and are subject to\nnumerous speculations, mainly relating to endocrine abnormal-\nities, immune disorders, oxidative stress, and aberrant gene\nexpression [ 8, 9].\nFerroptosis is a novel form of regulated cell death that is distinct\nfrom accidental cell death; it can be mediated by different\nmolecular signalling pathways [ 10, 11]. Speci fically, ferroptosis is\ndefined as an iron-dependent regulated form of necrosis that is\ncaused by massive lipid peroxidation-mediated membrane\ndamage, and this regulated necrosis plays a crucial role in the\ndevelopment and disease of various organisms [ 12, 13]. Although\nmany open questions remain in ferroptosis research, numerous\nreports have stated that ferroptosis is closely related to many\nReceived: 18 April 2023 Revised: 31 July 2023 Accepted: 14 August 2023\n1Department of Gynecology of Traditional Chinese Medicine, the First Af filiated Hospital of Naval Medical University, 200433 Shanghai, China. 2Department of Pharmaceutical\nSciences, Beijing Institute of Radiation Medicine, 100850 Beijing, China. 3These authors contributed equally: Yangshuo Li, Yalun He, Wen Cheng. 4These authors jointly supervised\nthis work: Zhexin Ni, Chaoqin Yu. ✉email: nizxzg@163.com; chqyu81@163.com\nwww.nature.com/cddiscovery\nOfficial journal of CDDpress\n1234567890();,:\n\ndiseases, such as cancer, ischaemic organ injury, and degenerative\ndiseases [14]. In several recent reports, ferroptosis was detected in\nectopic endometrial tissue in endometriosis characterized by\nperiodic haemorrhage [ 15] and in the early embryo in iron-\noverloaded peritoneal fluid [ 16]. However, the speci fic role and\nmechanism of ferroptosis in endometriosis, as well as in\nendometriotic infertility, remain unclear. In this article, we\nexplored the possible mechanisms of the formation of an iron-\noverloaded environment in endometriotic ectopic lesions, perito-\nneal fluid and follicular fluid. In addition, we summarized the main\npathways and regulatory mechanisms of ferroptosis and discussed\nits involvement in endometriosis and endometriosis-related\ninfertility to provide new insights into the discovery of novel\ntherapeutic targets.\nWe propose the notion that a threshold exists for the\noccurrence of ferroptosis in ectopic endometrial tissue in\nendometriosis. Once beyond the threshold, iron overload and\noxidative damage can lead to ferroptotic cell death. Multiple\noxidative and antioxidant systems can be activated simulta-\nneously and operate in parallel to adjust this threshold, which is\nimplicated in the metabolic reprogramming of the affected cells\n[17]. On the one hand, ectopic endometrial tissues in patients with\nendometriosis present resistance to ferroptosis, probably because\nof the shared antioxidant system in macrophages and ectopic\nlesion cells in the peritoneal fluid. On the other hand, ectopic\nendometrial tissue is partially subjected to ferroptosis, which\nseems bene ficial. However, this process is followed by the\nactivation of a series of downstream signalling pathways and\nthe release of cytokines that promote cell proliferation. Thus,\nectopic endometrial tissue might shift the threshold at which\nferroptosis occurs by metabolic reprogramming towards a\nproliferative advantage for itself, something that seems to be\nsimilar to that of cancer cells. However, the speci fic metabolic\ncheckpoints of the altered thresholds need further exploration,\nwhich is a future research direction.\nFERROPTOSIS\nDixon et al. first de fined ferroptosis as a distinct iron-dependent\nform of non-apoptotic cell death in 2012 [ 11]. Ferroptosis is\nmorphologically, biochemically, and genetically distinct from\nnecrosis, apoptosis, and autophagy, and these differing features\ninclude abnormal mitochondrial membrane density, iron accumu-\nlation, lipid peroxidation, overexpression of ferroptosis biomar-\nkers, and death of leucocyte subsets and the corresponding loss of\nimmune function [ 11, 18–21]. Of note, ferroptosis that occurs\nwithin a cell can spread in a population of cells in a peroxidized\nlipid and iron-dependent manner [ 22]. Overall, the core molecular\nmachinery of ferroptosis is regulated by various cellular signalling\npathways and genes but is primarily mediated through two main\npathways, namely, extrinsic or transporter-dependent pathways\n(e.g., reduced cysteine or glutamine uptake and increased iron\nuptake) and intrinsic or enzyme-regulated pathways (e.g., inhibi-\ntion of glutathione (GSH) peroxidase 4 (GPX4) antioxidant system)\n(Fig. 1).\nGPX4 pathway\nGPX4 is a key factor in the antioxidant system that is regulated by\nmultiple molecular mechanisms. In most cells, cysteine is obtained\nthrough the system xc- antiporter, which exchanges extracellular\nFig. 1 Molecular machinery and regulation of ferroptosis. The molecular machinery of ferroptosis involves cellular antioxidant and oxidative\nsystems, and the regulation of ferroptosis includes iron metabolism and lipid peroxidation.\nY. Li et al.\n2\nCell Death Discovery           (2023) 9:306 \n\ncystine with intracellular glutamate [ 23]. However, the deletion of\nthe cystine/glutamate antiporter SLC7A11 in mice is well tolerated\nunder unstressed environments [ 24], indicating that average cells\nhave a low intake requirement for cystine. The activity of\nexogenously ingested cystine and glutamate –cysteine ligase\n(GCL) can regulate the synthesis of GSH, which is a major\nendogenous antioxidant [ 11, 25]. When GSH exerts an antioxidant\neffect, GSH can act as an electron donor and oxidize itself to the\nglutathione disul fide (GSSG) form. The GSH/GSSG ratio usually\nindicates the level of cellular oxidative stress, which accelerates\nthe conversion of GSH to GSSG and decreases the GSH/GSSG\nratio [ 26].\nBased on its unique functions, GPX4 is considered a powerful\nantagonist of ferroptosis and plays a crucial role in regulating\nferroptosis. As a key antioxidant system enzyme, GPX4 can\ncatalyse the reduction in lipid peroxides in complex cellular\nmembrane environments [ 27]. It can detoxify cellular lipid\nperoxidation by using the cofactor (GSH) by converting complex\ntoxic lipid hydroperoxides, such as phospholipid hydroperoxides\nand cholesterol hydroperoxides, into their corresponding nontoxic\nlipid alcohols. The outcome is that GPX4 reduces the accumulation\nof ROS and acts against complex lipid peroxidation to reduce cell\ndeath [ 27, 28]. In addition, GPX4 is a kind of selenoprotein.\nTherefore, GPX4 synthesis is regulated by selenium (Se). Se\nprotects neurons by activating the transcription factors TFAP2c\nand Sp1 coordinately. This, in turn, upregulates GPX4 and other\ngenes to prevent fatal seizures [ 29]. Moreover, supplementation\nwith Se could enhance the expression of GPX4 in follicular helper\nT cells and increase the number of helper T cells to improve the\nantibody responsiveness of immunized mice after vaccination\n[30], indicating that the regulation of Se on GPX4 plays an\nessential role in normal mammalian embryos. Selenocysteine (Sec)\nis the substitution of Se for sulfur from cysteine, which can\nenhance the resistance of GPX4 to irreversible peroxidation and\nprevent hydroperoxide-induced ferroptosis [ 13, 31].\nThroughout the antioxidant system, the regulation of multiple\ninhibitors and ferroptosis inducers has been implicated. Inhibition\nof the GCL by buthionine sulfoximine (BSO) induces ferroptosis\nalone or enhances the sensitivity of cells to ferroptosis induced by\nother agents [ 32]. The activity of SLC7A11 is regulated by several\nfactors, such as the transcription factor activating transcription\nfactor 4 (ATF4) and/or nuclear factor erythroid 2-related 2 (NRF2)\n[33, 34], the epigenetic regulation-associated enzyme BAP1 [ 35],\nthe tumour suppressor protein p53 [ 36], the autophagy mechan-\nism component BECN1 [ 37], and the ferroptosis inducer erastin\n[38]. RSL3 can directly inhibit GPX4 activity but not its precursor\nGSH [ 27]. However, FINO2 indirectly inhibits GPX4 enzymatic\nfunction and directly induces ferrous (Fe\n2+) production [ 39].\nMitochondria-related pathways\nReactive oxygen species (ROS) are a byproduct of aerobic\nmetabolism that are mainly derived from mitochondrial metabo-\nlism and nicotinamide adenine dinucleotide phosphate (NADPH)\noxidase (NOX) on the cell membrane, and excessive ROS or the\ninappropriate location of ROS can damage cells [ 40]. ROS\nproduction in the mitochondria has been shown to be the\nsignalling pathway that regulates the immune response and\nautophagy but is also important for the induction of ferroptosis\n[41, 42]. Mitochondria can promote the progression of cysteine-\ndeprivation-induced ferroptosis but not inhibit GPX4-induced\nferroptosis [ 18]. The metabolic network of ROS production can\nparticipate in ferroptosis. The transporter SLC38A1 and the amino\nacid transporter SLC1A5-mediated glutamine uptake and subse-\nquent glutaminase 2 (GLS2)-mediated glutamate production are\nrequired for cysteine-deprivation-induced ferroptosis [ 43, 44].\nGlutamate generates α-ketoglutarate ( αKG) in mitochondria\nthrough transamination by the transaminase GOT1 [ 44]. αKG can\ngenerate acetyl-CoA, a metabolic precursor for lipid synthesis in\nthe cytoplasm, and stimulate dihydrolipoamide dehydrogenase to\nproduce mitochondrial ROS and increase local iron levels to\npromote ferroptosis [ 45]. In addition, the tricarboxylic acid cycle or\nelectron transfer chain in the mitochondria can promote lipid ROS\naccumulation and is involved in cysteine-deprivation-induced\nferroptosis [ 18]. However, ferristatin-1 can speci fically prevent\nferroptosis induced by erastin, but mitochondria are not involved\nin the function of ferristatin-1, suggesting that mitochondria may\nnot be necessary for ferroptosis [ 46].\nNotably, the voltage-depende nt anion channel (VDAC) in the\nmitochondrial outer membrane, also known as the mitochon-\ndrial pore, acts as a gatekeeper for the entry and exit of\nmitochondrial metabolites and is a convergence point for its\nbinding to various ligands and proteins to mediate various cell\nsurvival and cell death signals [ 47]. Erastin can directly bind to\nVDAC 2 and alter mitochondrial membrane permeability,\nthereby inducing nonap optotic cell death [ 48]. Iron –sulfur\ncluster protein CDGSH iron sulfur domain (CISD) 1, a mitochon-\ndrial outer membrane protein, regulates VDAC in a redox-\ndependent manner in cells and closes mitochondrial pores to\nprevent iron accumulation in the mitochondria [ 49]. Nedd4 can\nbe induced upon erastin treatment in melanoma cells, and\nNedd4 leads to VDAC 2/3 ubiquitination and mitochondrial\npore degradation [ 50]. These findings all illustrate that VDAC\nplays an important role in ferroptosis.\nRegulation of ferroptosis\nIron-related pathways. Iron is an indispensable metal for the body\nand is essential for maintaining biological homoeostasis. Iron\noxidation has two states, Fe\n2+ and ferric (Fe 3+), which are mainly\npresent intracellularly and extracellularly, respectively. The intercon-\nversion between Fe 2+ and Fe 3+ can either donate or accept\nelectrons. This is a process that p rovides the premise for redox\nreactions and may affect the sensitivity of cells to ferroptosis.\nInterestingly, only iron, and not other metals, such as zinc, that also\ncause ROS generation via the Fenton reaction [ 51], can induce\nferroptosis. Fe\n3+ c a nb i n dt ot r a n s f e r r i n( T F )i ns e r u ma n di s\nsubsequently taken up by the TF receptor 1 (TfR1), which is encoded\nby TFRC on the cell membrane [52]. Similarly, lactotransferrin (LTF) on\ncancer cell membranes promotes ferroptosis by increasing intracel-\nlular iron levels [ 53]. Protein kinase C-mediated heat shock protein\nbeta-1 (HSPB1) phosphorylation can stabilize the actin cytoskeleton,\nthereby inhibiting TfR1-mediatediron uptake and reducing lipid ROS\nproduction to limit ferroptotic cell death [ 54]. Subsequently, Fe\n3+\ntaken up into the cell is reduced to Fe2+ by STEAP3 metalloreductase\nin the endosome and is then released into the labile iron pool of the\ncytoplasm by divalent metal transporter 1 (DMT1) [ 55]. Fe\n2+\nparticipates in various cellular met abolic and biochemical reactions\nand maintains cellular homoeostasis. The NFS1 cysteine desulfurase\ncan promote iron–sulfur cluster biosynthesis. This results in increased\nFe\n2+ availability to inhibit erastin-induced ferroptosis in lung tumour\ncells and attenuates dihydroartemisinin-induced ferroptosis in\nleukaemia cells [55, 56]. The CISD1 protein and CISD2 protein, which\nare present in mitochondria and the endoplasmic reticulum (ER),\ninhibit ferroptosis by reducing iron uptake from mitochondria and\nROS production, respectively [57, 58]. The iron storage protein ferritin\nconsists of ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1)\nand functions to store iron in cells [ 59]. This protein can create an\niron-overloaded environment and lay the foundation for the\noccurrence of cellular ferroptosis. Interestingly, RSL3-induced ferrop-\ntosis could be inhibited by higher expression levels of mitochondrial\nferritin under hypoxic conditions [60]. Moreover, the nuclear receptor\ncoactivator 4 (NCOA4)-mediated selective autophagy pathway\n(ferritinophagy) increases cellular labile iron pool levels to promote\nthe rapid intracellular accumulat ion of ROS, which is critical for\nferroptosis [61].\nFerroportin1 (FPN1), the only identified mammalian nonhaem iron\nexporter, can transport Fe\n2+ from intracellular to extracellular spaces\nY. Li et al.\n3\nCell Death Discovery           (2023) 9:306 \n\n[62], and Fe 2+ is subsequently oxidized to Fe 3+ by the ferroxidase\nceruloplasmin (CP) [ 63]. Erastin can decrease FPN1 expression\nand induce iron accumulation in ec topic endometrial stromal cells\n(ESCs) of women with endometriosis to promote ferroptosis [ 38].\nKnockdown of FPN1 can promote ferroptosis in Alzheimer’sd i s e a s e\n(AD) and induce AD-like hippocampal atrophy and memory deficits.\nFurthermore, differentially expressed genes of the ferroptosis-\nassociated RNA-seq dataset are highly enriched in gene sets\nassociated with AD [ 62]. Moreover, prominin-2, a member of the\nprominin family of pentaspan membrane glycoproteins, can mediate\nthe release of ferritin into the extracellular space by exosomes in\nbreast epithelial and breast cancer cells, thereby promoting cellular\nresistance to ferroptosis [64].\nLipid metabolism pathways . Lipids are not only important\ncomponents of cell membranes but also precursors of various\nmolecules that play important biological roles. However, the\nexcessive accumulation of lipids has potentially toxic effects on\nindividual cells, as well as on the whole body. Previous studies\nsuggest that the peroxidation of polyunsaturated fatty acids in\nphospholipids by lipoxygenases (ALOX) is particularly important for\nferroptosis [ 65, 66]. After lipid peroxidation occurs, the initiated\ngeneration of lipid hydroperoxides (LOOH) and subsequent\ngeneration of malondialdehyde (MDA) and 4-hydroxynonenal\n(4HNE) increase during ferroptosis, leading to a sustained oxidative\nstress response [ 67, 68]. Arachidonic acid (AA) and adrenic acid\n(AdA) are the main substrates of lipid peroxidation in ferroptosis\n[19], and the lipid peroxidation process involves three enzymes,\nnamely, acyl-CoA synthetase long-chain family member 4 (ACSL4),\nlysophosphatidylcholine acyltransferase 3 (LPCAT3), and ALOX.\nACSL4 binds to AA/AdA and catalyses the formation of AA/AdA-\nCoA; this is followed by the LPCAT3-mediated esteri fication of AA/\nAdA-CoA to phospholipids (PL). Finally, ALOX catalyses the\ngeneration of LOOH from PL to promote ferroptosis [ 69].\nCytochrome P450 (CYP450) oxidoreductase can promote lipid\nperoxidation by accelerating the cycling between Fe\n2+ and Fe3+ in\nthe CYP450 haem fraction and is identified as the alternative source\nof ROS that induces ferroptosis-related lipid peroxidation [70]. Lipid\ndroplets (LDs) generated from the ER can store lipids in cells and\nsupply lipids for cellular metabolism. The LD cargo receptor RAB7A\ncan mediate selective autophagy (lipophagy) to degrade LDs,\nwhich increases the production of free fatty acids and promotes\nlipid peroxidation. Thus, it ultimately leads to ferroptosis [ 71].\nSummary. Under normal physiological conditions, iron plays an\nimportant role in metabolic processes. However, whenever the\ntransporter is mutated or deleted, it will disrupt the iron balance\nand lead to excessive accumulation, triggering cellular oxidative\ndamage and death [ 72, 73]. Similarly, ROS produced in normal\nphysical processes play an important role in the maintenance of cell\nfunction, but excessive ROS may cause metabolic disorders, such as\nlipid peroxidation, and induce ferroptosis [ 74, 75]. GPX4 can inhibit\nferroptosis by virtue of its special restorative function. Its depletion\ncan lead to a decrease in the antioxidant capacity of cells and\nincrease their sensitivity to ferroptosis [ 76]. In addition, as an\nNADPH-dependent coenzyme Q (CoQ) oxidoreductase, apoptosis-\ninducing factor mitochondria-associated 2 (AIFM2) can use NADPH\nto catalyse the regeneration of CoQ10 and act synergistically with\nGPX4 and GSH to inhibit phospholipid peroxidation and ferroptosis\n[77, 78]. GTP cyclohydrolase-1 (GCH1) can catalyse GTP to\ntetrahydrobiopterin to exert endogenous antioxidant effects and\ninhibit ferroptosis [79]. Dihydroorotate dehydrogenase (DHODH) is\na flavin-dependent mitochondrial enzyme that can work in parallel\nwith GPX4 to resist mitochondrial ferroptosis [80]. The upregulation\nof the tumour suppressor gene P53 leads to the accumulation of\nlipid hydroperoxides by inhibiting the expression of SLC7A11 and\nreducing the level of GSH, eventually triggering ferroptosis [ 81].\nFerroptosis is regulated by various factors and pathways.\nIn short, ferroptosis is an iron-dependent lipid peroxidation form\nof regulated cell death. Iron metabolism and lipid generation,\nstorage, and degradation are all closely associated with ferroptosis.\nExcessive free iron levels and dysregulated lipid metabolism in cells\ntrigger ferroptosis, but the oxidative and antioxidant systems are\nalso involved in the regulation and maintenance of cellular\nprocesses. In addition, ferroptosis is regulated by many other\nfactors. The complex mechanisms involved need to be elucidated\nfurther to help us better modulate the degree of ferroptosis caused\nby drugs or gene regulation for the treatment of diseases.\nIRON-OVERLOADED ENVIRONMENT IN ENDOMETRIOSIS\nEndometriosis can be divided into three phenotypes due to the\ndiverse of underlying aetiologies: super ficial peritoneal endome-\ntriosis, ovarian endometriosis, and deep in filtrating endometriosis\n[82]. Studies have shown that the levels of iron, ferritin, and\nhaemoglobin are higher in the peritoneal fluid of women with\nendometriosis than in that of normal women [ 83]. Moreover, iron\naggregates are present in endometriotic lesions of women with\nendometriosis and model mice [ 84, 85]. In addition, ovarian\nendometriomas contain high amounts of free iron, and the\nsurrounding follicles nearby are also iron overloaded, which\nadversely affects oocyte development and quality [ 86]. However,\nthe original cause of the iron-overloaded environment in ectopic\nlesions, peritoneal fluid, and follicular fluid of endometriosis is still\nunknown and may be related to the excessive degradation of red\nblood cells and increased in flux caused by menstrual re flux and\nrepeated bleeding of local lesions [ 87].\nRetrograde menstruation and ectopic endometrial bleeding\nlesions can transport menstrual endometrial tissue and red blood\ncells to the peritoneal cavity. Some of these tissues and cells will\nbe phagocytized, absorbed, and degraded by peritoneal macro-\nphages and stored in the form of haemosiderin. Additionally,\nferritin and haemoglobin are released into the peritoneal fluid\n[83]. The haem released by the hydrolytic digestion of haemoglo-\nbin is catabolized by haem oxygenase to generate active iron and\nforms iron-ferritin deposition. This overwhelms the iron homo-\neostasis and iron clearance system, finally leading to an iron-\noverloaded environment in peritoneal fluid and ectopic lesions of\nendometriosis [ 88]. In the environment of intraperitoneal iron\noverload, excess iron is transported by peripheral TF to cells within\nthe ovary. This iron can bind to TfR1 on the surface of cells and\ntrigger endocytosis [ 89]. In addition, menstrual re flux to the ovary\nand repeated bleeding in local lesions of the ovary may also lead\nto an iron-overloaded environment in follicular fluid. Excessive\naccumulation of intraperitoneal iron can lead to the overproduc-\ntion of ROS and the enhanced activation of nuclear factor-kappaB\n(NF-κB). This enhances the migration ability of human endome-\ntriotic cells by promoting the expression of matrix metalloprotei-\nnases (MMPs), aggravating in flammation, angiogenesis, and cell\nadhesion to participate in the progression of endometriosis\nlesions [ 59]. Moreover, iron overload in follicular fluid can cause\ngranulosa cell death and affect oocyte maturation and quality,\nultimately increasing the risk of endometriosis-related infertility\n[89, 90].\nFERROPTOSIS AND ENDOMETRIOSIS\nThe crosstalk between ferroptosis and in flammation\nEndometriosis is a chronic in flammatory disease that is closely\nrelated to in flammation and the immune response. As a regulated\nform of cell death, ferroptosis can activate different downstream\npathways and complex molecular effector mechanisms, leading to\ncell lysis in different forms and resulting in morphological changes\nand immune responses [ 10].\nAs the main substrate of lipid peroxidation released from PL in\nthe cell membrane, AA is a precursor of proin flammatory\nY. Li et al.\n4\nCell Death Discovery           (2023) 9:306 \n\nmediators that can be metabolized by cyclooxygenases (COX),\nALOX, and CYP450 monooxygenases to synthesize biologically\nactive in flammatory mediators, such as prostaglandins (PGs) and\nleukotrienes [ 91]. Interestingly, ferroptosis induced by erastin or\nRSL3 can increase the expression of PTGS2 encoding COX2 [ 27].\nThus, ferroptosis can promote AA metabolism and in flammatory\ncytokine secretion via COX2 synthesis. The inactivation of the\nferroptosis regulator GPX4, which can upregulate 12/15-ALOX and\nCOX1 expression [ 92, 93], may accelerate AA metabolism and\nfurther promote in flammatory responses. Conversely, the release\nof inflammatory cytokines promotes the progression of ferroptotic\ncell death, such as the inhibition of GPX4 expression in tumour\nnecrosis factor- α-treated cells (Fig. 2)[ 94]. Thus, there is crosstalk\nbetween ferroptosis and in flammation.\nSimilar to nonsilent immune forms of regulated necrosis,\nferroptotic cell death can release damage-associated molecular\npatterns (DAMPs) that promote the development of multiple\ninflammatory diseases and trigger the innate immune system.\nThese DAMPs can drive tissue in flammation and in flammation\ncrosstalk with ferroptosis. This further promotes an autoampli fica-\ntion loop that exaggerates in flammation and cell death and leads\nto a more severe degree of cell death and a range of in flammation-\nrelated responses [95, 96]. For example, high mobility group box 1\n(HMGB1), as a DAMP, is released in an autophagy-dependent\nmanner by ferroptosis inducers and mediates in flammatory\nresponses through the HMGB1-advanced glycation end-product-\nspecific receptor (AGER) pathway, a pathway that activates the NF-\nκB pathway in innate immunity [ 94]. This promotes the expression\nof MMPs and aggravates in flammation, angiogenesis, and cell\nadhesion in endometriosis.\nDouble-edged roles of ferroptosis in endometriosis\nEndometriosis is also an oestrogen-dependent gynaecological\ndisease in which excessive oestrogen signalling transduction and\naltered oestrogen signalling pathways play an important role in its\npathogenesis, resulting in oestrogen dominance and progester-\none resistance [ 97, 98]. Oestrogen dependence may be due to the\nupregulation of the 17 β-hydroxysteroid dehydrogenase-1 and\naromatase genes, whereas progesterone resistance may result\nfrom the failure of progesterone receptor activation and\ntranscription of progesterone target genes [ 99]. In normal\nendometrial tissue, oestrogen may inhibit autophagy in the\nendometrium by inhibiting the hypoxia-inducible factor-1/ROS/\nAMP-activated protein kinase signalling pathway and further\nactivating mammalian target of rapamycin complex (mTOR)\nsignalling during nonmenstrual periods [ 100]. However, the level\nof ROS is no longer suppressed by oestrogen in ectopic\nendometrial tissue cells. Thus, the level of ROS in ectopic\nendometrium is notably higher than that in normal eutopic\nendometrium. Perhaps this is because of the iron-overloaded\nenvironment in ectopic tissue cells [ 101].\nThe imbalance of iron metabolism plays an important role in\nthe pathogenesis of endometriosis, and studies have con firmed\nthat iron overload exists in the peritoneal fluid of patients with\nendometriosis [ 83, 102]. This phenomenon may be related to\nthe increased degradation of red blood cells caused by\nFig. 2 The crosstalk between ferroptosis and in flammation. AA is released from PL by in flammatory stimuli or by intercellular lipid\nperoxidation. The ALOX, COX, and CYP450 pathways promote further AA metabolization to in flammatory mediators. COX2 expression is\nincreased by ferroptosis. ALOX can promote ferroptosis by catalysing the generation of LOOH. The large array of oxidized lipid mediators\nreleased by ferroptosis can contribute to the activity of COX and ALOX. GPX4 inhibits the activity of ALOX and COX directly by decreasing cellular\nredox states. Ferroptosis initiates in flammatory responses by releasing DAMPs that are immunogenic. Several proin flammatory cytokines play\nimportant roles in the crosstalk between ferroptosis and inflammation. For example, TNF can inhibit the activity of GPX4 to promote ferroptosis.\nY. Li et al.\n5\nCell Death Discovery           (2023) 9:306 \n\nmenstrual re flux [ 87]. Overloaded iron generates a large\namount of ROS by inducing the Fenton reaction, forming an\nimbalance between antioxidants and leading to oxidative stress\nreactions such as cellular oxidative damage [ 83]. Therefore,\nectopic endometrial cell proliferation [ 103], the in flammatory\nresponse in the peritoneal cavity [ 104] and damage to the ovary\nand its cortex develop [ 105]. This iron-overloaded and\nperoxidative environment cre ates the conditions for the\nferroptosis of ectopic endometrial tissue to occur in endome-\ntriosis. Li et al. found that a ferroptosis inducer could induce\nferroptosis in ectopic endome trial stromal cells through\nferroportin-mediated iron accu mulation and then alleviate the\nectopic lesions of endometriosis. However, the inducer had\nlittle effect in normal endometrial stromal cells [ 38]. The\ndifference might be closely related to the special microenvir-\nonment of iron overload in ectopic endometrial stromal cells.\nHowever, the role of ferroptosis in endometriosis appears to be\nbidirectional. On the one hand, ferroptosis inducers can promote\nferroptosis in ectopic endometrial stromal cells, and thus, these\ninducers may become potential drugs for the treatment of\nendometriosis. On the other hand, ferroptotic endometrial stromal\ncells can release in flammatory cytokines and activate downstream\nregulatory pathways to promote proliferation and angiogenesis in\nsurrounding tissues. Iron overload in ectopic endometrial stromal\ntissues from patients with ovarian endometriosis-induced ferrop-\ntosis, which promoted fibrosis and tissue adhesions, and the\nprocess was associated with endometrial stromal cell subpopula-\ntions [ 106]. In a recent study, Li et al. found that ferroptosis in\nectopic endometrial stromal cells in patients with ovarian\nendometriosis could activate the p38 mitogen-activated protein\nkinase (p38 MAPK)/signal transducer and activator of transcription\n(STAT) 6 signalling pathway, thereby promoting local upregulation\nof vascular endothelial growth factor A (VEGFA) and interleukin-8\n(IL-8) in ectopic lesions [ 15]. VEGFA and IL-8 could promote cell\nproliferation, adhesion, and angiogenesis of ectopic endometrial\ntissue, thereby promoting the development of endometriosis\n[107, 108]. In addition, ferroptosis, as a form of in flammatory cell\ndeath, is associated with the release of DAMPs, which can trigger\nthe innate immune system and activate the NF- κB pathway\nthrough AGER [ 95, 109]. The excess of Fe\n2+ in ectopic ESCs\ngenerates ROS via the Fenton reaction, which contributes to the\nmigration abilities of MMPs via the ROS-NF- κB pathway in ectopic\nendometrial cells [ 59]. The overproduction of ROS alters gene\nexpression by regulating the redox-sensitive transcription factor\nNF-κB. NF- κB-mediated gene transcription in endometriotic cells\npromotes in flammation invasion, angiogenesis, and cell prolifera-\ntion and inhibits the apoptosis of endometriotic cells. These\neffects favour the development and maintenance of endome-\ntriosis [ 110, 111].\nIron overload and ferroptosis do occur in endometriotic lesions,\nand the use of ferroptosis inducers may be a potential treatment\nfor endometriosis. However, a series of downstream in flammatory\npathways activated after ferroptosis cannot be ignored, and these\npathways further promote angiogenesis and focal fibrosis (Fig. 3).\nTherefore, in the process of developing ferroptosis-related drugs\nwith the potential to target endometriosis, a series of downstream\nreactions caused by ferroptosis in ectopic endometrial tissue\nshould be considered, and these issues need to be further\nresolved in the future.\nMACROPHAGE FERROPTOSIS AND ENDOMETRIOSIS\nFerroptosis releases DAMPs and lipid oxidation products, which\naffect nonleukocytes and cause in flammatory cell death.\nFig. 3 Ectopic endometrial cells in iron-overloaded peritoneal fluid in endometriosis. Iron-overloaded peritoneal fluid results in excess Fe 2+\nin ectopic endometrial cells. Excess Fe 2+ generates ROS via the Fenton reaction, which contributes to ferroptosis in ectopic endometrial cells.\nEctopic endometrial cells promote angiogenesis and cell proliferative adhesion through downstream DAMPs and the P38 MAPK/STAT6\npathways of ferroptosis. Created with BioRender.com.\nY. Li et al.\n6\nCell Death Discovery           (2023) 9:306 \n\nHowever, it also mediates immune cell death that leads to\nlosses of immune function, s uch as macrophage function.\nMacrophages phagocytose aged erythrocytes and process iron\nfrom erythrocytes to participate in iron metabolism. Excessive\nerythrophagocytosis leads to iron overload in macrophages and\ninduces iron-dependent ferroptosis. Iron overload in bone\nmarrow-derived macrophages can upregulate SLC7A11 expres-\nsion via the ROS-NRF2-antioxidan tr e s p o n s ee l e m e n t( A R E )a x i s\nto reduce cellular sensitivity to ferroptosis [ 112]. In contrast,\nmice with GPX4-de ficient bone marrow macrophages are\nsusceptible to cell death caused by polymicrobial infection\n[113]. Furthermore, the release of DAMPs mediated by\nferroptosis can affect macrophage polarization, and polariza-\ntion imbalance can lead to various diseases or in flammatory\nconditions. For example, Kras\nG12D released from autophagy-\ndependent ferroptotic cancer cell death can limit the anti-\ntumour effects of macrophages by activating STAT3-mediated\nAGER-dependent M2 macrophage polarization [ 114]. Similarly,\nferroptosis-mediated cell death that results in the release of\n8-hydroxylamine (8-OHG) activates the STING1-dependent\ninflammatory pathway in surrounding macrophages and\npromotes M2 polarization [ 115]. Thus, ferroptosis directly\nimpairs macrophages through the release of DAMPs.\nMacrophages play an indispensable role in the chronic\ninflammatory disease mechanism of endometriosis. Previous\nstudies have shown that macrophages allow the growth of\nectopic endometrial tissue, promote angiogenesis, and recruit\nnerve fibres to contribute to chronic pain [ 101]. In the human\nperitoneal cavity, macrophages consist of 50% leucocytes [ 116].\nUnlike other cells that acquire Fe\n2+ through TfRC and DMT1, the\nmajor source of iron for macrophages is through the disposal of\nhaem-derived iron. Although macrophages have a remarkable\nability to tolerate iron overload [ 117], the antioxidant capacity\no fm a c r o p h a g e si si n s u fficient to cope with iron overload in this\nsetting. This ultimately leads to the outcome of ferroptosis due\nto excessive phagocytosis of eryt hrocytes and ferritinophagy\n[118]. Activated M1 macrophages are more sensitive to\nferroptosis than M2 macrophages, and this difference is\nassociated with inducible nitric oxide synthase in M1 macro-\nphages [ 119]. Therefore, iron overload in the peritoneal fluid\nmay promote M2 macrophage polarization, inhibit the M1\nmacrophage phenotype and induce a subset of macrophage\nferroptosis. Recent findings suggest that the M2 macrophage\nphenotypes with tissue repair effects predominate in the\nperitoneal fluid in women with endometriosis [ 120]. Therefore,\nthe peritoneal environment po ssibly promotes ectopic endo-\nmetrial tissue proliferation and growth by in fluencing macro-\nphage M2 polarization via iron overload, which releases anti-\ninflammatory cytokines, growth factors, and other reparative\ncomponents [ 121]. In summary, the intrinsic association\nbetween macrophages and endo metriosis is much less well-\nstudied than that for other diseases, such as cancer. The\nmechanisms by which macrophages resist ferroptosis help\nprovide us with new insights into the mechanisms of ferroptosis\nin the endometriosis model.\nFERROPTOSIS AND ENDOMETRIOSIS-RELATED INFERTILITY\nThe iron-overloaded environment induced by retrograde men-\nstruation is suspected to be an important factor in inducing the\ncontinued proliferation of ectopic endometrial tissue. In addition,\nferroptosis promoted by an iron-overloaded environment appears\nto be detrimental to oocytes or embryos and is also closely related\nto endometriosis-related infertility. Peritoneal fluid and follicular\nfluid are the external microenvironments for oocyte maturation\nand blastocyst formation, and these abnormal microenvironments\naffected by iron overload may lead to impaired reproductive\nfunction.In recent years, studies on the role and mechanism of\niron overload and ferroptosis in endometriosis-related infertility\nhave been reported successively (Table 1).\nIron overload in peritoneal fluid can affect embryonic\ndevelopment by leading to embryo toxicity and ferroptosis.\nChen et al. showed that the pelvic iron-overloaded environment\nin patients with endometrios is impaired early embryonic\ndevelopment and caused embryo toxicity by triggering GPX4\ndownregulation-dependent fer roptosis in preimplantation\nTable 1. Studies on the association of iron overload and ferroptosis with endometriosis-related infertility.\nAuthor,\ndate (Ref.)\nModel Research content Main results Final outcomes\nChen et al.,\n2021 [ 104]\nIn vivo: C57BL/6J female mice\nIn vitro: mouse two-cell stage\nembryos\nIron overload in\nendometriosis\nperitoneal fluid\nDisrupted mitochondrial function,\ndecreased ATP levels, increased ROS levels,\nhyperpolarized MMP , triggered apoptosis\nand ferroptosis\nCompromised\npreimplantation mouse\nembryo development\nLi et al.,\n2021 [ 16]\nIn vivo: C57BL/6J female mice\nIn vitro: mouse two-cell stage\nembryos\nIron overload in\nendometriosis\nperitoneal fluid\nDisrupted blastocyst formation, decreased\nGPX4 expression, disrupted mitochondrial\nfunction, decreased ATP levels, increased\nROS levels and hyperpolarized MMP ,\nupregulated HMOX1\nEmbryotoxicity and early\nembryo ferroptosis\nNi et al.,\n2022 [ 110]\nIn vivo: Kunming female mice\nIn vitro: mouse granulosa cells and\nhuman granulosa cells\nIron overload in\nendometriosis\nfollicular fluid\nDecreased GPX4 and GSH expression,\nincreased NCOA4 expression, NCOA4-\nmediated ferritinophagy, released\nexosomes of granulosa cell containing\nabnormal miRNAs\nFerroptosis of granulosa\ncells and oocyte\ndysmaturity\nLi et al.,\n2020 [ 109]\nIn vitro: mouse oocytes Transferrin\ninsufficiency and iron\noverload in\nendometriosis\nfollicular fluid\nReduced concentration of transferrin with\nthree analogues, increased concentration\nof ferricion, decreased maturation in vitro\nrate of mouse oocytes\nOocyte dysmaturity\nHu et al.,\n2021 [ 111]\nIn vitro: porcine oocytes Iron overload-induced\nferroptosis in porcine\noocytes\nIncreased intracellular ROS generation,\ndecreased intracellular free thiol levels,\ninduced mitochondrial dysfunction,\ntriggered autophagy, decreased embryonic\ndevelopmental potential\nImpaired oocyte meiosis,\ndecreased oocyte quality\nand embryonic\ndevelopmental\ncompetence\nDing et al.,\n2022 [ 112]\nIn vivo: C57BL/6J female mice Iron overload in\nendometriosis ovarian\nfunction\nIncreased MDA levels, decreased GPX4 and\nGSH expression, decreased growing\nfollicles numbers\nCellular ferroptosis,\ncompromised ovarian\nfunction\nY. Li et al.\n7\nCell Death Discovery           (2023) 9:306 \n\nmouse embryos. This leads to endo metriosis-related infertility\nand adverse pregnancy outcomes [ 122]. During this process,\nexcess iron could induce the excessive accumulation of ROS,\nwhich leads to oxidative stress and damages mitochondrial\nfunction in preimplantation mouse embryos. This triggers ATP\ngeneration impairment and decreases mitochondrial mem-\nbrane potential (MMP) levels. Moreover, the expression of GPX4\nin embryos was signi ficantly decreased [ 122]. GPX4 is essential\nfor embryonic development. GPX4 de ficiency results in abnor-\nmal embryonic development compared to the de ficiencies of all\nother GPX family members and ultimately produces lethal\nphenotypes in mice [ 123]. In addition to disrupting mitochon-\ndrial function, the iron-overload environment in the peritoneal\nfluid of endometriosis could also reduce the expression of GPX4\nand induce lipid peroxidation. Thus, blastocyst formation is\ndisrupted, and embryo toxicity and ferroptosis occur. The\nferroptosis inhibitor Fer-1 could improve these adverse condi-\ntions [ 16]. In addition, haem oxygenase 1 (HMOX1) is\nupregulated in embryonic ferroptosis, and inhibition of HMOX1\ncan maintain normal mitochondrial function, thereby prevent-\ning ferroptosis from occurring [ 16] .T h u s ,H M O X 1m a yp l a ya n\nimportant role in mediating embryo ferroptosis. Its overexpres-\nsion can play a pro-oxidative role and induce ferroptosis by\nincreasing Fe accumulation and lipid peroxidation [ 124, 125].\nThe total iron levels and ferritin and TfR1 expression levels in\nendometrioma-proximal follicles are higher than those in\nendometrioma-distal follicles and healthy ovarian follicles. More-\nover, the oocyte retrieval rates in endometrioma-proximal and\n-distal follicles are lower than those in healthy ovarian follicles\n[126]; this illustrates that excessive iron intake by follicles leads to\ncytotoxic accumulation that affects normal oocyte development.\nIn recent research, Li et al. studied speci fic proteins at different\nconcentrations in the follicular fluid of patients with advanced\nendometriosis and found that the transferrin concentration of the\nthree analogues of cDNA FLJ53691, cDNA FLJ54111, and TRF\nvariant Fragment in the follicular fluid decreased. The iron ion\nconcentration of these analogues increased. The environment of\ntransferrin deficiency and iron overload could increase the level of\nROS and lead to oxidative stress. Thus, the in vitro maturation rate\nof mouse oocytes could signi ficantly decrease, which might be\none of the causes of endometriosis-related infertility [ 89]. Ni et al.\nfound that iron-overloaded follicular fluid could trigger ferroptosis\nin granulosa cells and immaturity of oocytes, thereby increasing\nthe risk of endometriosis-related infertility [ 90]. The iron-\noverloaded environment of follicular fluid could not only inhibit\nthe expression of GPX4 and its upstream regulatory target GSH\nbut also cause the high expression of NCOA4 in granulosa cells.\nThis would lead to NCOA4-dependent ferritinophagy, which\nincreases lipid peroxidation in granulosa cells and promotes\nferroptosis. Moreover, granulosa cells undergoing ferroptosis\ncannot exert nutritional and paracrine functions on oocytes and\ncan release granulosa cell exosomes containing abnormal miRNAs.\nTherefore, oocyte maturation is inhibited, and endometriosis-\nrelated infertility can develop. The iron chelators deferoxamine\nmesylate and VITE could change these circumstances by increas-\ning GPX4 expression and decreasing iron overload [ 90].\nFig. 4 Oocyte and granulosa cells in iron-overloaded follicular fluid in endometriosis. Iron-overloaded follicular fluid in endometriosis plays\nan important role in the progression of endometriosis-related infertility. Iron overload in peritoneal fluid affects the mitochondrial function of\noocytes and decreases GPX4 expression, thereby inducing ferroptosis and toxicity by promoting lipid peroxidation. Moreover, iron overload in\nfollicular fluid not only decreases GPX4 and GSH expression, but also increases NCOA4 expression and mediates ferritinophagy. Thus,\ngranulosa cell ferroptosis is induced by promoting lipid peroxidation. Granulosa cells undergoing ferroptosis cause oocyte dysmaturity by\nreleasing exosomes containing abnormal miRNAs. These situations can contribute to endometriosis-related infertility. Created with\nBioRender.com.\nY. Li et al.\n8\nCell Death Discovery           (2023) 9:306 \n\nFurthermore, after in vitro ferroptosis inducer ferric ammonium\ncitrate (FAC) intervention, mammalian oocytes experienced\nincreases in ROS and autophagy-related protein LC3 and\nmitochondrial dysfunction. Additionally, there was signi ficant\naccumulation of Fe 2+ in the cytoplasm and decreases in the\npolar body (PB) expulsion rate and blastocyst formation rate. Thus,\nexogenous ferroptosis inducer-induced ferroptosis inhibits oocyte\nmeiosis by increasing oxidative stress, inducing mitochondrial\ndysfunction, triggering autophagy splitting process and affecting\noocyte quality [ 127]. Conversely, the inhibition of ferroptosis\nmight not only inhibit the progression of endometriosis, but also\nimprove the adverse effects of iron overload on ovarian function,\nthereby improving fertility and becoming a therapeutic approach\nfor endometriosis-related infertility [ 128].\nIn summary, these findings suggest that iron overload and its\ninduced ferroptosis in peritoneal fluid and follicular fluid in\npatients with endometriosis play an important role in the\nprogression of endometriosis-related infertility (Fig. 4). Therefore,\nmitigating the impact of iron stress on the local microenviron-\nment, such as the use of antioxidant agents or iron chelators, is\nexpected to be an effective approach for the prevention and\ntreatment of endometriosis-related infertility.\nCONCLUSION\nIn recent years, researchers have gradually appreciated and revealed\nthe potential role of ferroptosis in endometriosis. These findings\nhighlight the ability of ectopic endometrial tissue to resist iron\noverload-induced ferroptosis and promote ectopic lesion growth by\nmediating local cellular ferroptosis in peritonealfluid in patients with\nendometriosis. However, oocytes from patients with endometriosis-\nrelated infertility are threatened by iron overload, and the\ndevelopment and maturation of oocytes are affected and prone\nto trigger cellular ferroptosis. This is possibly due to the immature\nantioxidant system and membrane repair mechanisms of the\noocyte. Furthermore, although iron accumulation and lipid perox-\nidation are unique intermediate events in the onset of ferroptosis,\nthey are not the ultimate executors. Lipid peroxidation can also\noccur in other cell death types, which depend on different ultimate\neffectors. Key regulators of ferroptosis can also regulate other types\nof cell death. 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Blood.\n2016;127:139–48.\nAUTHOR CONTRIBUTIONS\nYL, YH, and WC contributed equally to the literature review in preparation for writing.\nYL, YH, and ZZ conducted the image production and manuscript editing. ZN and CY\nreviewed and supervised the manuscript. All authors have contributed to the\nmanuscript and approved the submitted version.\nFUNDING\nThis work was supported by the National Natural Science Foundation of China [grant\nnumber 82074206], the Science and Technology Innovation Action Plan of Shanghai\nScience and Technology Commission [grant number 21Y21920500] and Changhai\nHospital “Gu Hai ” plan.\nCOMPETING INTERESTS\nThe authors declare no competing interests.\nADDITIONAL INFORMATION\nCorrespondence and requests for materials should be addressed to Zhexin Ni or\nChaoqin Yu.\nReprints and permission information is available at http://www.nature.com/\nreprints\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims\nin published maps and institutional af filiations.\nOpen Access This article is licensed under a Creative Commons\nAttribution 4.0 International License, which permits use, sharing,\nadaptation, distribution and reproduction in any medium or format, as long as you give\nappropriate credit to the original author(s) and the source, provide a link to the Creative\nCommons license, and indicate if changes were made. The images or other third party\nmaterial in this article are included in the article ’s Creative Commons license, unless\nindicated otherwise in a credit line to the material. If material is not included in the\narticle’s Creative Commons license and your intended use is not permitted by statutory\nregulation or exceeds the permitted use, you will need to obtain permission directly\nfrom the copyright holder. To view a copy of this license, visit http://\ncreativecommons.org/licenses/by/4.0/.\n© The Author(s) 2023\nY. Li et al.\n11\nCell Death Discovery           (2023) 9:306","source_license":"CC0","license_restricted":false}