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      Recent progress in ferroptosis: inducers and inhibitors

      review-article
      1 , 1 , 2 ,
      Cell Death Discovery
      Nature Publishing Group UK
      Cancer metabolism, Targeted therapies

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          Abstract

          Ferroptosis is a new iron-dependent form of programmed cell death characterized by iron accumulation and lipid peroxidation. In recent years, ferroptosis has garnered enormous interest in disease treatment research communities in pursuit to reveal the mechanism and key targets of ferroptosis because ferroptosis is closely related to the pathophysiological processes of many diseases. Recent studies have shown some key targets, such as glutathione peroxidase 4 (GPX4) and System Xc , and several inducers and inhibitors have been developed to regulate these key targets. With the emergence of new ferroptosis targets, studies on inducers and inhibitors have made new developments. The selection and use of inducers and inhibitors are very important for related work. This paper briefly introduces important regulatory targets in the ferroptosis metabolic pathway, lists and categorizes commonly used and recently developed inducers and inhibitors, and discusses their medical application. The paper ends of with potential future research direction for ferroptosis.

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          Most cited references113

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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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            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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              ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

              Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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                Author and article information

                Contributors
                z.guo@bnu.edu.cn
                Journal
                Cell Death Discov
                Cell Death Discov
                Cell Death Discovery
                Nature Publishing Group UK (London )
                2058-7716
                29 December 2022
                29 December 2022
                2022
                : 8
                : 501
                Affiliations
                [1 ]GRID grid.20513.35, ISNI 0000 0004 1789 9964, Center for Biological Science and Technology, Guangdong Zhuhai-Macao Joint Biotech Laboratory, Advanced Institute of Natural Sciences, , Beijing Normal University, ; Zhuhai, China
                [2 ]GRID grid.20513.35, ISNI 0000 0004 1789 9964, Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, , Beijing Normal University, ; Beijing, China
                Author information
                http://orcid.org/0000-0002-4443-9360
                Article
                1297
                10.1038/s41420-022-01297-7
                9800531
                36581640
                5d14eebd-6f70-449c-a58e-836accad53a9
                © The Author(s) 2022

                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
                : 3 October 2022
                : 20 December 2022
                : 22 December 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 31860259
                Award Recipient :
                Funded by: Beijing Normal University via the Youth Talent Strategic Program Project (310432102) Guangdong Provincial University Featured Innovation Project (2021KTSCX365)
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2022

                cancer metabolism,targeted therapies
                cancer metabolism, targeted therapies

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