Heme induced progesterone-resistant profiling and promotion of endometriosis in vitro and in vivo

Ma, Xiao-Qian; Liu, Yuyin; Zhong, Zhiqi; Chen, Siman; Hu, Wenting; Sheng, Yan-Ran; Liu, Yukai; Wei, Chunyan; Li, Ming‐Qing; Zhu, Xiao‐Yong

doi:10.1016/j.bbadis.2023.166761

Cited by 7 publications

(13 citation statements)

References 57 publications

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“…In the subcellular organelles level, progesterone receptor membrane components (PGRMC 1/2) conduct heme transport. 9 Heme oxygenase (HO) is the rate-limiting enzyme in heme catabolism, predominantly expressed in the endoplasmic reticulum (ER) of macrophages. HO exists in three isoforms, of which HO-1 is particularly significant due to its elevated expression in EM.…”

Section: Impaired Erythrocytes Go Through Erythrophagocytosis By Cd36mentioning

confidence: 99%

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Heme metabolism and HO‐1 in the pathogenesis and potential intervention of endometriosis

Hou,

Lu,

Zhang

et al. 2024

American J Rep Immunol

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Endometriosis (EM) is one of the diseases related to retrograded menstruation and hemoglobin. Heme, released from hemoglobin, is degraded by heme oxygenase‐1 (HO‐1). In EM lesions, heme metabolites regulate processes such as inflammation, redox balance, autophagy, dysmenorrhea, malignancy, and invasion, where macrophages (Mø) play a fundamental role in their interactions. Regulation occurs at molecular, cellular, and pathological levels. Numerous studies suggest that heme is an indispensable component in EM and may contribute to its pathogenesis. The regulatory role of heme in EM encompasses cytokines, signaling pathways, and kinases that mediate cellular responses to external stimuli. HO‐1, a catalytic enzyme in the catabolic phase of heme, mitigates heme's cytotoxicity in EM due to its antioxidant, anti‐inflammatory, and anti‐proliferative properties. Certain compounds may intervene in EM by targeting heme metabolism, guiding the development of appropriate treatments for all stages of endometriosis.

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Section: Impaired Erythrocytes Go Through Erythrophagocytosis By Cd36mentioning

confidence: 99%

“…The latest study demonstrates that heme conveys a progesterone-resistant effect. 9 Researchers have identified compounds that influence heme metabolism in endometriosis and associated endometrial diseases. New ideas for more treatment strategies may derive from these hypotheses.…”

mentioning

confidence: 99%

Heme metabolism and HO‐1 in the pathogenesis and potential intervention of endometriosis

Hou,

Lu,

Zhang

et al. 2024

American J Rep Immunol

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“…Ovarian endometrioma cyst fluid contains abundant amounts of hemoglobin, heme, and iron. 28 Iron causes persistent oxidative stress, whereas elevated heme synthesis leads to increased mitochondrial OXPHOS, electron transport, and energy (ATP) generation in cancer cells 13 and endometrial stromal cells (ESCs) 29 (Figure 1③). Recent in vitro and animal studies revealed that heme induces the growth of endometriotic lesions through the mitochondrial OXPHOS pathway.…”

Section: Energy Metabolism In Endometriosismentioning

confidence: 99%

“…Recent in vitro and animal studies revealed that heme induces the growth of endometriotic lesions through the mitochondrial OXPHOS pathway. 29 Mitochondrial respiration and glycolysis are positively and negatively regulated by heme, respectively. 30 Therefore, energy metabolism in endometriosis may be strongly dependent on its surrounding microenvironment, that is, the degree of hypoxia and the amount of hemoglobin degradation products.…”

Section: Energy Metabolism In Endometriosismentioning

confidence: 99%

“…34 Multiple reports have shown that GPX is downregulated in endometriosis. [35][36][37][38][39] Tissue expression and activity of GPX were evaluated using immunohistochemistry 29,39 and enzymatic assay, [35][36][37] respectively. Furthermore, PRDX1 reduces hydrogen peroxide and alkyl hydroperoxides and protects cells against oxidative stress.…”

Section: Redox Homeostasis In Endometriosismentioning

confidence: 99%

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The role of mitochondrial dynamics in the pathophysiology of endometriosis

Kobayashi,

Matsubara,

Yoshimoto

et al. 2023

J of Obstet and Gynaecol

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AimEndometriosis is a chronic disease of reproductive age, associated with pelvic pain and infertility. Endometriotic cells adapt to changing environments such as oxidative stress and hypoxia in order to survive. However, the underlying mechanisms remain to be fully elucidated. In this review, we summarize our current understanding of the pathogenesis of endometriosis, focusing primarily on the molecular basis of energy metabolism, redox homeostasis, and mitochondrial function, and discuss perspectives on future research directions.MethodsPapers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this narrative literature review.ResultsMitochondria serve as a central hub sensing a multitude of physiological processes, including energy production and cellular redox homeostasis. Under hypoxia, endometriotic cells favor glycolysis and actively produce pyruvate, nicotinamide adenine dinucleotide phosphate (NADPH), and other metabolites for cell proliferation. Mitochondrial fission and fusion dynamics may regulate the phenotypic plasticity of cellular energy metabolism, that is, aerobic glycolysis or OXPHOS. Endometriotic cells have been reported to have reduced mitochondrial numbers, increased lamellar cristae, improved energy efficiency, and enhanced cell proliferation and survival. Increased mitochondrial fission and fusion turnover by hypoxic and normoxic conditions suggests an activation of mitochondrial quality control mechanisms. Recently, candidate molecules that influence mitochondrial dynamics have begun to be identified.ConclusionThis review suggests that unique energy metabolism and redox homeostasis driven by mitochondrial dynamics may be linked to the pathophysiology of endometriosis. However, further studies are needed to elucidate the regulatory mechanisms of mitochondrial dynamics in endometriosis.

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Creatine Promotes Endometriosis by Inducing Ferroptosis Resistance via Suppression of PrP

Chen,

Ma,

Liu

et al. 2024

Advanced Science

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Endometriosis, a chronic inflammatory disease, significantly impairs the quality of life of women in their reproductive years; however, its pathogenesis remains poorly understood. The accumulation of retrograde menstruation and recurrent bleeding fosters a high‐iron environment in ectopic lesions, triggering ferroptosis in ectopic endometrial stromal cells (EESCs), thereby hindering the establishment of endometriosis. However, abnormal EESCs demonstrate resistance to ferroptosis in high‐iron environments, promoting the progression of this disease. Here, novel findings on the accumulation of creatine, derived from endogenous synthesis, in both peritoneal fluid and EESCs of patients with endometriosis are presented. Creatine supplementation reduces cellular iron concentrations, mitigating oxidative stress and lipid peroxidation, thereby enhancing cell viability and preventing ferroptosis under high‐iron conditions. Utilizing the drug affinity–responsive target stabilization (DARTS) assay, prion protein (PrP) as a potential creatine‐sensing protein is identified. Mechanistically, creatine binds to the active site of PrP, inhibits the conversion of trivalent iron to divalent iron, and decreases iron uptake, promoting the tolerance of EESCs to ferroptosis. This interaction contributes to the development of endometriosis. The novel association between creatine and ferroptosis provides valuable insights into the role of creatine in endometriosis progression and highlights its potential as a therapeutic target for endometriosis.

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Heme induced progesterone-resistant profiling and promotion of endometriosis in vitro and in vivo

Cited by 7 publications

References 57 publications

Heme metabolism and HO‐1 in the pathogenesis and potential intervention of endometriosis

Heme metabolism and HO‐1 in the pathogenesis and potential intervention of endometriosis

The role of mitochondrial dynamics in the pathophysiology of endometriosis

Creatine Promotes Endometriosis by Inducing Ferroptosis Resistance via Suppression of PrP

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