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      Ferroptosis: past, present and future

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          Abstract

          Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases.

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          Ferroptosis: process and function.

          Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.
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            Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.

            Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
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              Recent Progress in Ferroptosis Inducers for Cancer Therapy

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                Author and article information

                Contributors
                wgilu79@163.com
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                3 February 2020
                3 February 2020
                February 2020
                : 11
                : 2
                : 88
                Affiliations
                [1 ]ISNI 0000 0004 1797 9737, GRID grid.412596.d, Department of Pancreatic and Biliary Surgery, , The First Affiliated Hospital of Harbin Medical University, ; Harbin, Heilongjiang Province China
                [2 ]ISNI 0000 0004 1797 9737, GRID grid.412596.d, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, , The First Affiliated Hospital of Harbin Medical University, ; Harbin, China
                [3 ]ISNI 0000 0004 0632 3337, GRID grid.413259.8, General Surgery Department, , Xuanwu Hospital, Capital Medical University, ; Beijing, China
                [4 ]Department of General Surgery, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161005 China
                [5 ]ISNI 0000 0000 8877 7471, GRID grid.284723.8, Department of General Surgery, Affiliated Qiqihar Hospital, , Southern Medical University, ; Qiqihar, Heilongjiang 161007 China
                Author information
                http://orcid.org/0000-0003-2061-7430
                Article
                2298
                10.1038/s41419-020-2298-2
                6997353
                32015325
                f57ec7c7-4b70-474c-979d-2f59f58c07fb
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 November 2019
                : 15 January 2020
                : 22 January 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100011002, National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund);
                Award ID: No.81770639
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100009592, Beijing Municipal Science and Technology Commission;
                Award ID: No. Z191100006619038
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100002799, Capital Medical University (CMU);
                Award ID: No.1192070312
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2020

                Cell biology
                cell death,cell signalling
                Cell biology
                cell death, cell signalling

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