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

Abstract

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.

How Can Selected Dietary Ingredients Influence the Development and Progression of Endometriosis?

“…Large amounts of this trace element have been detected not only in ectopic lesions [ 105 , 113 , 114 ] but also in peritoneal fluid [ 115 ], follicular fluid [ 91 , 116 , 117 ], and blood [ 118 ] collected from patients with endometriosis. Additionally, suggestions indicating the involvement of Fe in the malignant transformation of OMA [ 119 ], dysmenorrhea [ 120 ], or the formation of adhesions [ 121 ] further emphasize the important role of Fe in the pathogenesis of endometriosis. Unfortunately, despite such an important role of Fe in the course of endometriosis and numerous studies assessing its impact on the development of the disease, no reports link Fe with diet.…”

The Regulatory Mechanism and Research Progress of Ferroptosis in Gastric Cancer

“… 55 Research on the mechanism of ferroptosis has focused on the effects of oxidative damage, the direction of iron metabolism regulation, and related targets. 47 , 56 Studies have shown that cell sensitivity to ferroptosis can be changed by regulating the intracellular iron content, and the combination of ferroptosis therapy with radiotherapy, chemotherapy, and targeted therapy for gastric cancer has shown good therapeutic effects in vivo and in vitro. 16 , 57 , 58 Identifying the downstream signal transduction or iron-dependent ROS production pathways using specific indicators would further clarify the ferroptosis mechanism and distinguish ferroptosis from other types of cell death, which has recently become a research focus, and the ferroptosis mechanism can be distinguished from other mechanisms involved in iron metabolism, oxidative damage, and other diseases-related processes to suggest new research ideas and treatment, which shows important clinical significance.…”

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

“…On the other hand, ferroptotic endometrial stromal cells can release inflammatory cytokines and activate downstream regulatory pathways to promote proliferation and angiogenesis in surrounding tissues. Iron overload in ectopic endometrial stromal tissues from patients with ovarian endometriosis-induced ferroptosis, which promoted fibrosis and tissue adhesions, and the process was associated with endometrial stromal cell subpopulations [ 106 ]. In a recent study, Li et al found that ferroptosis in ectopic endometrial stromal cells in patients with ovarian endometriosis could activate the p38 mitogen-activated protein kinase (p38 MAPK)/signal transducer and activator of transcription (STAT) 6 signalling pathway, thereby promoting local upregulation of vascular endothelial growth factor A (VEGFA) and interleukin-8 (IL-8) in ectopic lesions [ 15 ].…”