Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis

Li, Guojing; Lin, Yeong-Jer; Zhang, Yili; Gu, Ni-Hao; Yang, Bingxin; Shan, Shan; Liu, Na; Ouyang, Jing; Yang, Yu; Sun, Feng; Xu, Hong

doi:10.1038/s41420-022-00821-z

Cited by 43 publications

(44 citation statements)

References 51 publications

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“…The obtained results suggested that ferroptosis is enhanced in ectopic stromal tissue of women with EMs fibrosis. Similar to our results, Li G et al found that endometrial stromal cell ferroptosis promotes angiogenesis in EMs (Li et al, 2022). Consequently, it is speculated that there is an underlying relationship between iron deposition, enhanced ferroptosis, and excessive fibrosis.…”

Section: Discussionsupporting

confidence: 92%

“…Ferroptosis was first described as a form of iron-dependent programmed cell death in cancer by the Stockwell research group in 2012, in which the hallmark is the contribution of iron to the development of lipid peroxidation and oxidative cell damage (Dixon et al, 2012). Although it is well established that iron overload can trigger ferroptosis, the results of previous studies on ferroptosis resistance and ferroptosis in endometrial lesions are paradoxical (Ng et al, 2020;Li et al, 2021;Li et al, 2022). How iron-induced ferroptosis exerts an influence on EMs fibrosis is not yet elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Ferroptosis induced by iron overload promotes fibrosis in ovarian endometriosis and is related to subpopulations of endometrial stromal cells

et al. 2022

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Endometriosis (EMs) is defined as the presence of tissue somewhat resembling endometrial glands and stroma outside the uterus; the retrograded endometrium grows in the peritoneal cavity and elicits fibrosis. Ferroptosis is a recently discovered form of programmed cell death, which is iron-dependent. The induction of ferroptosis has been found to participate in fibrosis. However, the relationship between EMs fibrosis and ferroptosis remains unknown. In this study, we confirmed that the iron content in ectopic stromal tissue in ovarian EMs is significantly increased. We explored the role of iron-induced ferroptosis in the pathogenesis of ovarian EMs fibrosis for the first time. We found that ferroptosis in ectopic tissues was significantly enhanced than that in eutopic tissues. Furthermore, we performed in vivo drug screening and found that ferroptosis induced by ferric ammonium citrate (FAC) could aggravate fibrosis. To clarify the mechanism of this process, the stromal composition of human uterine endometrium and endometrial tissue was characterized. Fibroblast-specific protein-1 was used for fibroblasts, smooth muscle actin alpha for myofibroblasts, and platelet-derived growth factor receptor beta (CD140b) for mesenchymal stromal cells (MSCs). The results demonstrated that the percentage of myofibroblasts was higher and the portion of MSCs was lower in ectopic endometrial stroma than those in eutopic endometrium. Moreover, the proportion of MSCs decreased significantly and the percentage of myofibroblasts increased considerably after FAC treatment in vitro. However, disruption of intracellular iron levels or ferroptosis via chelation of intracellular iron deferoxamine mesylate or ferroptosis inhibitor ferrostatin-1 could reverse this process, indicating that iron-induced ferroptosis plays a vital role in ovarian EMs fibrosis. Considering that iron accumulation can feed the Fenton reaction to generate unquenchable amounts of free radicals, causing ferroptosis and tissue damage and thereby contributing to fibrosis, we validated the underlying mechanism that excess iron can facilitate fibrotic responses. Collectively, these data provide evidence that supernumerary iron is a key regulator in promoting MSCs ferroptosis and inducing ovarian EMs fibrosis.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Ferroptosis induced by iron overload promotes fibrosis in ovarian endometriosis and is related to subpopulations of endometrial stromal cells

et al. 2022

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“…Our study demonstrates the harm of an iron overload environment to the oocyte, and relevant studies have proposed that iron overload-induced ferroptosis impairs oocyte maturation and development [ 49 ]. Iron overload was thought to play an important contributory role in shaping the EMs inflammatory microenvironment and cell adhesion [ 6 , 15 , 27 ]. Combined with our findings, iron chelators, and VITE can be used for the treatment of EMs-related infertility.…”

Section: Discussionmentioning

confidence: 99%

“…Ectopic endometrial stromal cells (EESCs) suppress ferroptosis and promote the proliferation and migration by regulating the expression of related proteins and long non-coding RNA [ 13 , 14 ]. Meanwhile, the occurrence of ferroptosis by local EESCs in contact with cyst fluid promotes angiogenesis in EMs [ 15 ]. However, the mechanisms of ferroptosis in granulosa cells and oocytes in EMs have not been fully determined.…”

Section: Introductionmentioning

confidence: 99%

Iron-overloaded follicular fluid increases the risk of endometriosis-related infertility by triggering granulosa cell ferroptosis and oocyte dysmaturity

Ni¹,

Li²,

Song³

et al. 2022

Cell Death Dis

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Endometriosis (EMs) occurs in approximately 50% of women with infertility. The main causes of EMs-related infertility are follicle dysplasia and reduced oocyte quality. Iron overload occurs in ovarian follicular fluid (FF) of patients with EMs, and this condition is associated with oocyte maturation disorder. However, the underlying molecular mechanism remains largely unknown. In the present study, we identified the mechanism underlying ferroptosis in ovarian granulosa cells and oocyte maturation failure in EMs based on a retrospective review of in vitro fertilization/intracytoplasmic sperm injection-frozen embryo transfer outcomes in infertile patients with EMs. Mouse granulosa cells were treated with EMs-related infertile patients' follicular fluid (EMFF) in vitro. Western blot analysis, quantitative polymerase chain reaction, fluorescence staining, and transmission electron microscopy were used to assess granulosa cells ferroptosis. The effects of exosomes were examined by nanoparticle tracking analysis, RNA-seq, and Western blot analysis. Finally, the therapeutic values of vitamin E and iron chelator (deferoxamine mesylate) in vivo were evaluated in an EMs-related infertility model. Patients with ovarian EMs experienced poorer oocyte fertility than patients with non-ovarian EMs. We observed that EMFF with iron overload-induced granulosa cell ferroptosis in vitro and in vivo. Mechanically, nuclear receptor coactivator four-dependent ferritinophagy was involved in this process. Notably, granulosa cells undergoing ferroptosis further suppressed oocyte maturation by releasing exosomes from granulosa cells. In therapeutic studies, vitamin E and iron chelators effectively alleviated EMs-related infertility models. Our study indicates a novel mechanism through which EMFF with iron overload induces ferroptosis of granulosa cells and oocyte dysmaturity in EMs-related infertility, providing a potential therapeutic strategy for EMs-related infertility.

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“…These cells have an important role in disrupting adaptive immune responses and promoting tumor growth and progression [ 114 ]. In endometriosis, some stromal cells of the cyst walls underwent ferroptosis; however, endometrial stromal cell ferroptosis induced the production of angiogenic inflammatory and growth cytokines [ 115 ]. From these studies, it can be found that ferroptosis inhibits cancer development on the one hand and on the other hand leads to inflammation and cytokine secretion, thus promoting tumor progression.…”

Section: Ferroptosis In Cancer Therapeuticsmentioning

confidence: 99%

Ferroptosis and Its Multifaceted Role in Cancer: Mechanisms and Therapeutic Approach

et al. 2022

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Ferroptosis, a new type of non-apoptotic cell death modality, is different from other modes of cell death and has been primarily found in tumor cells. Previous studies have reported that ferroptosis can be triggered by specific modulators (e.g., drugs, nutrients, and iron chelators), leading to increased intracellular lipid reactive oxygen species (ROS) accumulation and iron overload. Recent reports have shown that ferroptosis at the cellular and organism levels can prevent an inflammatory storm and cancer development. Emerging evidence suggests potential mechanisms (e.g., system Xc-, glutathione peroxidase 4 (GPX4), lipid peroxidation, glutathione (GSH), and iron chelators) are involved in ferroptosis, which may mediate biological processes such as oxidative stress and iron overload to treat cancer. To date, there are at least three pathways that mediate ferroptosis in cancer cells: system Xc-/GSH/GPX4, FSP1/CoQ10/NAD(P)H, and ATG5/ATG7/NCOA4. Here, we summarize recent advances in the occurrence and development of ferroptosis in the context of cancer, the associations between ferroptosis and various modulators, and the potential mechanisms and therapeutic strategies targeting ferroptosis for the treatment of cancer.

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Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis

Cited by 43 publications

References 51 publications

Ferroptosis induced by iron overload promotes fibrosis in ovarian endometriosis and is related to subpopulations of endometrial stromal cells

Ferroptosis induced by iron overload promotes fibrosis in ovarian endometriosis and is related to subpopulations of endometrial stromal cells

Iron-overloaded follicular fluid increases the risk of endometriosis-related infertility by triggering granulosa cell ferroptosis and oocyte dysmaturity

Ferroptosis and Its Multifaceted Role in Cancer: Mechanisms and Therapeutic Approach

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