Ferroptosis: molecular mechanisms and health implications

Cell Research, Journal Year: 2020, Volume and Issue: 31(2), P. 107 - 125

Published: Dec. 2, 2020

Abstract Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form non-apoptotic cell in 2012, there has been mounting interest process and function ferroptosis. Ferroptosis occur two major pathways, extrinsic or transporter-dependent pathway intrinsic enzyme-regulated pathway. is caused by a redox imbalance between production oxidants antioxidants, which driven abnormal expression activity multiple redox-active enzymes that produce detoxify free radicals lipid oxidation products. Accordingly, precisely regulated at levels, including epigenetic, transcriptional, posttranscriptional posttranslational layers. The transcription factor NFE2L2 plays central role upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on integrated molecular machinery describe how dysregulated involved cancer, neurodegeneration, tissue injury, inflammation, infection.

Language: Английский

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Ferroptosis: machinery and regulation

Autophagy, Journal Year: 2020, Volume and Issue: 17(9), P. 2054 - 2081

Published: Aug. 19, 2020

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death caused by lipid peroxidation, which controlled integrated oxidation and antioxidant systems. The iron-containing enzyme lipoxygenase the main promoter ferroptosis producing hydroperoxides, its function relies on activation ACSL4-dependent biosynthesis. In contrast, selenium-containing GPX4 currently recognized as a central repressor ferroptosis, activity depends glutathione produced from cystine-glutamate antiporter SLC7A11. Many metabolic (especially involving iron, lipids, amino acids) degradation pathways (macroautophagy/autophagy ubiquitin-proteasome system) orchestrate complex ferroptotic response through direct or indirect regulation iron accumulation peroxidation. Although detailed mechanism membrane injury during remains mystery, ESCRT III-mediated plasma repair can make cells resistant to ferroptosis. Here, we review recent rapid progress in understanding molecular mechanisms focus epigenetic, transcriptional, posttranslational this process.Abbreviations: 2ME: beta-mercaptoethanol; α-KG: α-ketoglutarate; ccRCC: clear renal carcinoma; EMT: epithelial-mesenchymal transition; FAO: fatty acid beta-oxidation; GSH: glutathione; MEFs: mouse embryonic fibroblasts; MUFAs: monounsaturated acids; NO: nitric oxide; NOX: NADPH oxidase; PPP: pentose phosphate pathway; PUFA: polyunsaturated acid; RCD: death; RNS: reactive nitrogen species; ROS: oxygen RTAs: radical-trapping antioxidants; UPS: system; UTR: untranslated region.

Language: Английский

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Functions of N6-methyladenosine and its role in cancer

Molecular Cancer, Journal Year: 2019, Volume and Issue: 18(1)

Published: Dec. 1, 2019

N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A installed by methyltransferases, removed demethylases recognized reader proteins, regulate RNA metabolism including translation, splicing, export, degradation microRNA processing. Alteration levels participates cancer pathogenesis development via expression tumor-related genes like BRD4, MYC, SOCS2 EGFR. In this review, we elaborate recent advances research enzymes. We also highlight underlying mechanism progression. Finally, review corresponding potential targets therapy.

Language: Английский

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Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

Cellular & Molecular Biology Letters, Journal Year: 2020, Volume and Issue: 25(1)

Published: Feb. 27, 2020

Ferroptosis is a newly recognized type of cell death, which different from traditional necrosis, apoptosis or autophagic death. However, the position ferroptosis in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored intensively so far. In this study, we mainly analyzed relationship between and LPS-induced ALI.In human bronchial epithelial line, BEAS-2B, was treated with LPS ferrostatin-1 (Fer-1, inhibitor). The viability measured using CCK-8. Additionally, levels malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), iron, as well protein level SLC7A11 GPX4, were groups. To further confirm vitro results, an ALI model induced by mice, therapeutic action Fer-1 tissues evaluated.The BEAS-2B down-regulated treatment, together markers while MDA, 4-HNE total iron increased treatment dose-dependent manner, could be rescued Fer-1. results vivo experiment also indicated that exerted against ALI, tissues.Our study important role progression may become novel target patients.

Language: Английский

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Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: April 21, 2020

Ferroptosis is a kind of regulated cell death (RCD) caused by the redox state disorder intracellular microenvironment controlled glutathione peroxidase 4 (GPX4), which inhibited iron chelators and lipophilic antioxidants. In addition to classical regulatory mechanisms, new factors for ferroptosis have been discovered in recent years, such as P53 pathway, ATF3/4 Beclin 1 (BECN1) some non-coding RNA. closely related cancer treatment, neurodegenerative diseases, ischemia-reperfusion organ, neurotoxicity, other particular, field diseases treatment has aroused people's interest. The nuclear factor E2 2 (Nrf2/NFE2L2) proved play key role neurodegeneration disease regulation. promotes progression while expression Nrf2 its target genes (Ho-1, Nqo-1, Trx) declined with aging, therefore, there still insufficient evidence networks diseases. this review, we will provide brief overview well an emphasis on mechanism regulating ferroptosis. We also highlight during process investigate theoretical basis further research relationship between treatment.

Language: Английский

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Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death

Cells, Journal Year: 2020, Volume and Issue: 9(6), P. 1505 - 1505

Published: June 20, 2020

Ferroptosis is a new type of oxidative regulated cell death (RCD) driven by iron-dependent lipid peroxidation. As major sites iron utilization and master regulators metabolism, mitochondria are the main source reactive oxygen species (ROS) and, thus, play role in this RCD. is, indeed, associated with severe damage mitochondrial morphology, bioenergetics, metabolism. Furthermore, dysregulation metabolism considered biochemical feature neurodegenerative diseases linked to ferroptosis. Whether dysfunction can, per se, initiate ferroptosis whether function context-dependent still under debate. Cancer cells accumulate high levels ROS promote their metabolic activity growth. Of note, cancer rewiring often acquired sensitivity This strongly suggests that may act as an adaptive response imbalance constitute promising way eradicate malignant cells. Here, we review current literature on ferroptosis, discuss opportunities potentially use mitochondria-mediated strategy for therapy.

Language: Английский

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p53 in ferroptosis regulation: the new weapon for the old guardian

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 29(5), P. 895 - 910

Published: Jan. 27, 2022

Language: Английский

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The Application of Ferroptosis in Diseases

Pharmacological Research, Journal Year: 2020, Volume and Issue: 159, P. 104919 - 104919

Published: May 26, 2020

Language: Английский

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Regulating tumor suppressor genes: post-translational modifications

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: June 10, 2020

Abstract Tumor suppressor genes cooperate with each other in tumors. Three important tumor proteins, retinoblastoma (Rb), p53, phosphatase, and tensin homolog deleted on chromosome ten (PTEN) are functionally associated they regulated by post-translational modification (PTMs) as well. PTMs include phosphorylation, SUMOylation, acetylation, novel modifications becoming growing appreciated. Because most of reversible, normal cells use them a switch to control the state being resting or proliferating, also involve cell survival cycle, which may lead abnormal proliferation tumorigenesis. Although lot studies focus importance kind PTM, further discoveries shows that (TSGs) form complex “network” interaction modification. Recently, there several promising strategies for TSGs change more frequently than carcinogenic cancers. We here review necessity, characteristics, mechanisms Rb, PTEN, its influence precise selective function. discuss current antitumoral therapies p53 PTEN predictive, prognostic, therapeutic target cancer.

Language: Английский

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The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Feb. 27, 2020

Abstract Ferroptosis, a novel form of regulated cell death, is different from other types death in morphology, genetics and biochemistry. Increasing evidence indicates that ferroptosis has significant implications on linked to cardiomyopathy, tumorigenesis, cerebral hemorrhage name few. Here we summarize current literature ferroptosis, including organelle dysfunction, signaling transduction pathways, metabolic reprogramming epigenetic regulators cancer progression. With regard organelles, mitochondria-induced cysteine starvation, endoplasmic reticulum-related oxidative stress, lysosome dysfunction golgi stress-related lipid peroxidation all contribute induction ferroptosis. Understanding the underlying mechanism could provide insight into treatment various intractable diseases cancers.

Language: Английский

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