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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The molecular machinery of regulated cell death

Cell Research, Journal Year: 2019, Volume and Issue: 29(5), P. 347 - 364

Published: April 4, 2019

Cells may die from accidental cell death (ACD) or regulated (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms have been identified are increasingly being implicated in various human pathologies. Here, we critically review the current state art regarding types RCD, including necroptosis, pyroptosis, ferroptosis, entotic death, netotic parthanatos, lysosome-dependent autophagy-dependent alkaliptosis oxeiptosis. The in-depth comprehension each these lethal subroutines their intercellular consequences uncover therapeutic targets for avoidance pathogenic loss.

Language: Английский

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Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)¹

Autophagy, Journal Year: 2021, Volume and Issue: 17(1), P. 1 - 382

Published: Jan. 2, 2021

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered field. Our knowledge base relevant new technologies also been expanding. Thus, it is important to formulate on a regular basis updated monitoring autophagy different organisms. Despite numerous reviews, there continues be confusion regarding acceptable methods evaluate autophagy, especially multicellular eukaryotes. Here, present investigators select interpret examine related processes, reviewers provide realistic reasonable critiques reports that are focused these processes. These not meant dogmatic rules, because appropriateness any assay largely depends question being asked system used. Moreover, no individual perfect every situation, calling use multiple techniques properly monitor each experimental setting. Finally, several core components machinery implicated distinct autophagic processes (canonical noncanonical autophagy), implying genetic approaches block should rely targeting two or more autophagy-related genes ideally participate steps pathway. Along similar lines, proteins involved regulate other cellular pathways including apoptosis, all them can used as specific marker bona fide responses. critically discuss current assessing information they can, cannot, provide. ultimate goal encourage intellectual technical innovation

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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Ferroptosis, necroptosis, and pyroptosis in anticancer immunity

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: Aug. 10, 2020

Abstract In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by fact that only one third of patients with most types respond to these agents. The induction cell death mechanisms other than apoptosis gradually emerged as a new treatment strategy because tumors harbor innate resistance apoptosis. date, possibility combining two modalities not been discussed systematically. Recently, few studies revealed crosstalk between distinct and antitumor immunity. pyroptosis, ferroptosis, necroptosis combined showed synergistically enhanced activity, even ICI-resistant tumors. Immunotherapy-activated CD8+ T cells traditionally believed induce tumor via following main pathways: (i) perforin-granzyme (ii) Fas-FasL. identified mechanism which suppress growth inducing ferroptosis provoked review relationship system activation. Hence, this review, we summarize knowledge reciprocal interaction immunity mechanisms, particularly necroptosis, three potentially novel immunogenic death. Because evidence is derived from using animal models, also reviewed related bioinformatics data available for human tissues public databases, partially confirmed presence interactions activation

Language: Английский

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Ferroptosis: mechanisms and links with diseases

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Feb. 3, 2021

Abstract Ferroptosis is an iron-dependent cell death, which different from apoptosis, necrosis, autophagy, and other forms of death. The process ferroptotic death defined by the accumulation lethal lipid species derived peroxidation lipids, can be prevented iron chelators (e.g., deferiprone, deferoxamine) small lipophilic antioxidants ferrostatin, liproxstatin). This review summarizes current knowledge about regulatory mechanism ferroptosis its association with several pathways, including iron, lipid, cysteine metabolism. We have further discussed contribution to pathogenesis diseases such as cancer, ischemia/reperfusion, various neurodegenerative Alzheimer’s disease Parkinson’s disease), evaluated therapeutic applications inhibitors in clinics.

Language: Английский

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Iron Metabolism in Ferroptosis

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Oct. 7, 2020

Ferroptosis is a form of regulated cell death that characterized by iron-dependent oxidative damage and subsequent plasma membrane ruptures the release damage-associated molecular patterns. Due to role iron in mediating production reactive oxygen species enzyme activity lipid peroxidation, ferroptosis strictly controlled regulators involved many aspects metabolism, such as uptake, storage, utilization, efflux. Translational transcriptional regulation homeostasis provide an integrated network determine sensitivity ferroptosis. Impaired implicated various iron-related pathological conditions or diseases, cancer, neurodegenerative ischemia-reperfusion injury. Understanding mechanisms underlying metabolism during may effective strategies for treatment ferroptosis-associated diseases. Indeed, chelators effectively prevent occurrence ferroptosis, which new approaches disorders. In this review, we summarize recent advances theoretical modeling highlight therapeutic implications

Language: Английский

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Autophagy-Dependent Ferroptosis: Machinery and Regulation

Cell chemical biology, Journal Year: 2020, Volume and Issue: 27(4), P. 420 - 435

Published: March 10, 2020

Language: Английский

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Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Dec. 8, 2022

Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various activities, including clearance aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target development cancer medications recent years. However, because tumor show avoidance apoptosis, which causes treatment resistance recurrence, numerous studies been devoted alternative mortality processes, namely necroptosis, pyroptosis, ferroptosis, cuproptosis; these modalities extensively studied shown be crucial therapy effectiveness. Furthermore, evidence suggests that undergoing may alter immunogenicity microenvironment (TME) some extent, rendering it more suitable inhibiting progression metastasis. In addition, other components TME undergo abovementioned forms induce immune attacks on cells, resulting enhanced antitumor responses. Hence, this review discusses molecular processes features cuproptosis effects novel proliferation Importantly, introduces complex affect biology. It also summarizes potential agents nanoparticles or inhibit their therapeutic based from vivo vitro reports clinical trials inducers evaluated treatments patients. Lastly, we summarized impact modulating drug advantages adding modulators over conventional treatments.

Language: Английский

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Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein

Autophagy, Journal Year: 2020, Volume and Issue: 16(11), P. 2069 - 2083

Published: Jan. 10, 2020

is the most frequently mutated oncogene in human neoplasia. Despite a large investment to understand effects of KRAS mutation cancer cells, direct oncogenetic activation on immune cells remain elusive. Here, we report that extracellular

Language: Английский

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