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      Ferroptosis and its Role in Gastric Cancer

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          Abstract

          Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Currently, surgery is the treatment of choice for GC. However, the associated expenses and post-surgical pain impose a huge burden on these patients. Furthermore, disease recurrence is also very common in GC patients, thus necessitating the discovery and development of other potential treatment options. A growing body of knowledge about ferroptosis in different cancer types provides a new perspective in cancer therapeutics. Ferroptosis is an iron-dependent form of cell death. It is characterized by intracellular lipid peroxide accumulation and redox imbalance. In this review, we summarized the current findings of ferroptosis regulation in GC. We also tackled on the action of different potential drugs and genes in inducing ferroptosis for treating GC and solving drug resistance. Furthermore, we also explored the relationship between ferroptosis and the tumor microenvironment in GC. Finally, we discussed areas for future studies on the role of ferroptosis in GC to accelerate the clinical utility of ferroptosis induction as a treatment strategy for GC.

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          Most cited references119

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

            Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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              Regulation of ferroptotic cancer cell death by GPX4.

              Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                30 June 2022
                2022
                : 10
                : 860344
                Affiliations
                [1] 1 Nanjing University of Chinese Medicine , Nanjing, China
                [2] 2 Jiangsu Provincial Second Chinese Medicine Hospital , The Second Affiliated Hospital of Nanjing University of Chinese Medicine , Nanjing, China
                [3] 3 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica , School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing, China
                [4] 4 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor , Nanjing University of Chinese Medicine , Nanjing, China
                [5] 5 Department of Clinical Laboratory , Jiangsu Province Hospital of Chinese Medicine , Affiliated Hospital of Nanjing University of Chinese Medicine , Nanjing, China
                [6] 6 School of Basic Medical Sciences , Nanjing University of Chinese Medicine , Nanjing, China
                Author notes

                Edited by: Haiyang Zhang, Tianjin Medical University, China

                Reviewed by: Yihuang Gu, Nanjing University, China

                Zhengyu Li, Shanghai University of Traditional Chinese Medicine, China

                *Correspondence: Hongru Zhang, zhr5001@ 123456vip.163.com ; Zhiguang Sun, zhiguangsun@ 123456njucm.edu.cn
                [ † ]

                These authors have contributed equally to this work and share first authorship

                This article was submitted to Cell Death and Survival, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                860344
                10.3389/fcell.2022.860344
                9280052
                35846356
                740cb869-de0d-4638-a80a-9f201be3c328
                Copyright © 2022 Gu, Xia, Li, Zou, Lu, Ren, Zhang and Sun.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 January 2022
                : 28 March 2022
                Categories
                Cell and Developmental Biology
                Review

                ferroptosis,iron,gastric cancer,ros,microenvironment,drug resistance

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