FTH1 Inhibits Ferroptosis Through Ferritinophagy in the 6-OHDA Model of Parkinson's Disease

Tian, Ye; Lü, Juan; Hao, Xinchang; Li, Hang; Zhang, Guiyu; Liu, Xuelei; Li, Xinrong; Zhao, Caiping; Kuang, Weihong; Chen, Dongfeng; Zhu, Meiling

doi:10.1007/s13311-020-00929-z

Cited by 262 publications

(173 citation statements)

References 45 publications

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“…As a regulatory element of cellular iron storage, FTH1 is critical for maintaining intracellular iron homeostasis. Knockout of FTH1 is shown to induce ferroptosis through erastin, sorafenib, and other pathways in various disease models ( 37 ) while overexpression of FTH1 could restrain ferritinophagy to reduce ferroptosis ( 38 ). Moreover, FTH1-mediated iron metabolism disorder is shown to exacerbate myocardial damage during MI and reduce heart function ( 39 ).…”

Section: Resultsmentioning

confidence: 99%

Development and Validation of a Random Forest Diagnostic Model of Acute Myocardial Infarction Based on Ferroptosis-Related Genes in Circulating Endothelial Cells

Chen

Shi

2021

Front. Cardiovasc. Med.

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The high incidence and mortality of acute myocardial infarction (MI) drastically threaten human life and health. In the past few decades, the rise of reperfusion therapy has significantly reduced the mortality rate, but the MI diagnosis is still by means of the identification of myocardial injury markers without highly specific biomarkers of microcirculation disorders. Ferroptosis is a novel reported type of programmed cell death, which plays an important role in cancer development. Maintaining iron homeostasis in cells is essential for heart function, and its role in the pathological process of ischemic organ damages remains unclear. Being quickly detected through blood tests, circulating endothelial cells (CECs) have the potential for early judgment of early microcirculation disorders. In order to explore the role of ferroptosis-related genes in the early diagnosis of acute MI, we relied on two data sets from the GEO database to first detect eight ferroptosis-related genes differentially expressed in CECs between the MI and healthy groups in this study. After comparing different supervised learning algorithms, we constructed a random forest diagnosis model for acute MI based on these ferroptosis-related genes with a compelling diagnostic performance in both the validation (AUC = 0.8550) and test set (AUC = 0.7308), respectively. These results suggest that the ferroptosis-related genes might play an important role in the early stage of MI and have the potential as specific diagnostic biomarkers for MI.

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Section: Resultsmentioning

confidence: 99%

Development and Validation of a Random Forest Diagnostic Model of Acute Myocardial Infarction Based on Ferroptosis-Related Genes in Circulating Endothelial Cells

Chen

Shi

2021

Front. Cardiovasc. Med.

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“… 17 , 18 Recent studies demonstrate that ferritin is a key ferroptotic regulator, and its level affects the susceptibility to ferroptosis in vitro and in vivo . 19 − 21 In ferritinophagy, the cargo receptor NCOA4 directly recognizes and binds FTH1, then delivers iron-bound ferritin to autophagosomes for lysosomal degradation and iron release. It has been reported that ferritinophagy participates in ferroptosis.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action

et al. 2021

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Ferroptosis is an iron-dependent form of oxidative cell death, and the inhibition of ferroptosis is a promising strategy with which to prevent and treat neurological diseases. Herein we report a new ferroptosis inhibitor 9a with a novel mechanism of action. It is demonstrated that nuclear receptor coactivator 4 (NCOA4), a cargo receptor for ferritinophagy, is the target of 9a . Compound 9a blocks ferroptosis by reducing the amount of bioavailable intracellular ferrous iron through disrupting the NCOA4–FTH1 protein–protein interaction. Further studies indicate that 9a directly binds to recombinant protein NCOA4 383–522 and effectively blocks the NCOA4 383–522 –FTH1 interaction. In a rat model of ischemic stroke, 9a significantly ameliorates the ischemic-refusion injury. With the first ligand 9a , this work reveals that NCOA4 is a promising drug target. Additionally, 9a is the first NCOA4–FTH1 interaction inhibitor. This work paves a new road to the development of ferroptosis inhibitors against neurological diseases.

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“…The role of ferritin in preventing iron-mediated oxidative stress was observed in many studies reporting a direct correlation between modulation of FTH1 expression and dysregulation of iron homeostasis (75). Speci cally, a reduction in FTH1 expression leads to excess labile iron, in turn promoting the formation of oxygen-derived free radicals (39,67).…”

Section: Ros Levels Are Reduced Upon Fth1-gene Silencing In Hescsmentioning

confidence: 99%

Dissecting the Molecular Response of Human Escs to Iron-Mediated Oxidative Stress by Genetic Silencing of FTH1 Gene

Scaramuzzino¹,

Lucchino²,

Scalise³

et al. 2021

Preprint

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Background: Embryonic stem cells (ESCs) are pluripotent cells with indefinite self-renewal ability and differentiation properties. As such, to function properly and maintain genomic stability, ESCs need to be endowed with an efficient repair system as well as effective redox homeostasis. In this study, we investigated and characterized different aspects involved in ESCs response to iron accumulation following stable knockdown of ferritin heavy chain (FTH1) gene, encoding for a major iron storage protein with ferroxidase activity. Methods: stable FTH1 knockdown of H9-hES cell line was achieved with the use of shRNA lentiviral particles. Upon FTH1 silencing, we speculated whether hESCs still retained their pluripotency capability were first monitored for their capability the pluripotent status,FTH1 stable knock-down ESCs were obtained using lentiviral vector plasmids. The effect of FTH1 silencing on hESCs pluripotency was evaluated through alkaline phosphatase (AP) staining, immunofluorescence and embryoid bodies (EBs) formation assay. Western blotting and qRT-PCR analysis were performed to assess the involvement of nuclear factor (erythroid-derived-2)-like 2 (Nrf2) and pentose phosphate pathway (PPP) in the antioxidant response. ROS levels and mitochondrial functionality were explored by flow cytometry. Seahorse Analyzer was used to evaluate metabolic and bioenergetic profiles. Results: Our findings clearly show that FTH1 silencing in hESCs does not correlate with increased ROS production nor with redox status strengthening the concept that hESCs are extremely resistant and, to certain extent, even refractory to the pattern of results produced in other cell lines. Collectively, our results demonstrate that FTH1 silencing is accompanied by a significant activation of the nuclear factor (erythroid-derived-2)-like 2 (Nrf2) signaling pathway and pentose phosphate pathway (PPP) which crosstalk in driving hESCs antioxidant cascade events able to antagonize the effects of FTH1 silencing.Conclusion: to our knowledge, this is the first evidence of a crosstalk between FTH1 silencing and Nrf2 pathway activation in hESCs, casting a new light on how human ESCs perform under oxidative stress conditions. Our findings go beyond previous reports, showing how the Nrf2 pathway, in combination with PPP activation, regulates the molecular signature underlying ESCs defence mechanisms against oxidative stress mediated by FTH1 downregulation.

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FTH1 Inhibits Ferroptosis Through Ferritinophagy in the 6-OHDA Model of Parkinson's Disease

Cited by 262 publications

References 45 publications

Development and Validation of a Random Forest Diagnostic Model of Acute Myocardial Infarction Based on Ferroptosis-Related Genes in Circulating Endothelial Cells

Development and Validation of a Random Forest Diagnostic Model of Acute Myocardial Infarction Based on Ferroptosis-Related Genes in Circulating Endothelial Cells

Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action

Dissecting the Molecular Response of Human Escs to Iron-Mediated Oxidative Stress by Genetic Silencing of FTH1 Gene

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