O-Phenylenediamine: a privileged pharmacophore of ferrostatins for radical-trapping reactivity in blocking ferroptosis

2018 ◽  
Vol 16 (21) ◽  
pp. 3952-3960 ◽  
Author(s):  
Xie-Huang Sheng ◽  
Cheng-Cheng Cui ◽  
Chao Shan ◽  
Yu-Zhen Li ◽  
Duo-Hong Sheng ◽  
...  
Keyword(s):  
Cell Death ◽  
Lipid Hydroperoxides ◽  
Radical Trapping ◽  
Regulated Cell Death ◽  
Dependent Form

Ferroptosis is a non-apoptotic, iron dependent form of regulated cell death that is characterized by the accumulation of lipid hydroperoxides.

scholarly journals Positive and Negative Regulation of Ferroptosis and Its Role in Maintaining Metabolic and Redox Homeostasis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Ankita Sharma ◽  
Swaran Jeet Singh Flora
Keyword(s):  
Cell Death ◽  
Fatty Acid ◽  
Polyunsaturated Fatty Acid ◽  
Redox Homeostasis ◽  
Lipid Peroxide ◽  
Buthionine Sulfoximine ◽  
Lipid Hydroperoxides ◽  
Repair Capacity ◽  
Regulated Cell Death ◽  
Dependent Form

Ferroptosis is a recently recognized regulated form of cell death characterized by accumulation of lipid-based reactive oxygen species (ROS), particularly lipid hydroperoxides and loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). This iron-dependent form of cell death is morphologically, biochemically, and also genetically discrete from other regulated cell death processes, which include autophagy, apoptosis, necrosis, and necroptosis. Ferroptosis is defined by three hallmarks, defined as the loss of lipid peroxide repair capacity by GPX4, the bioavailability of redox-active iron, and oxidation of polyunsaturated fatty acid- (PUFA-) containing phospholipids. Experimentally, it can be induced by many compounds (e.g., erastin, Ras-selective lethal small-molecule 3, and buthionine sulfoximine) and also can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and deferoxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin and liproxstatin). The sensitivity of a cell towards ferroptotic cell death is tightly associated with the metabolism of amino acid, iron, and polyunsaturated fatty acid metabolism, and also with the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis sensitivity is also governed by many regulatory proteins, which also link ferroptosis to the function of key tumour suppressor pathways. In this review, we highlight the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its association with other cellular metabolic processes.

scholarly journals The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Lihong Mao ◽  
Tianming Zhao ◽  
Yan Song ◽  
Lin Lin ◽  
Xiaofei Fan ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Diseases ◽  
Therapeutic Strategy ◽  
Kidney Injury ◽  
Hepatic Disease ◽  
Therapeutic Concept ◽  
Regulated Cell Death ◽  
Dependent Form ◽  
Molecular Machinery

Abstract Ferroptosis is an iron- and lipotoxicity-dependent form of regulated cell death (RCD). It is morphologically and biochemically distinct from characteristics of other cell death. This modality has been intensively investigated in recent years due to its involvement in a wide array of pathologies, including cancer, neurodegenerative diseases, and acute kidney injury. Dysregulation of ferroptosis has also been linked to various liver diseases and its modification may provide a hopeful and attractive therapeutic concept. Indeed, targeting ferroptosis may prevent the pathophysiological progression of several liver diseases, such as hemochromatosis, nonalcoholic steatohepatitis, and ethanol-induced liver injury. On the contrary, enhancing ferroptosis may promote sorafenib-induced ferroptosis and pave the way for combination therapy in hepatocellular carcinoma. Glutathione peroxidase 4 (GPx4) and system xc− have been identified as key players to mediate ferroptosis pathway. More recently diverse signaling pathways have also been observed. The connection between ferroptosis and other forms of RCD is intricate and compelling, where discoveries in this field advance our understanding of cell survival and fate. In this review, we summarize the central molecular machinery of ferroptosis, describe the role of ferroptosis in non-cancer hepatic disease conditions and discuss the potential to manipulate ferroptosis as a therapeutic strategy.

scholarly journals Ferroptosis-Inducing Nanomedicine for Cancer Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yang Wang ◽  
Tianfu Liu ◽  
Xiang Li ◽  
Hui Sheng ◽  
Xiaowen Ma ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cancer Therapy ◽  
Future Perspective ◽  
Oxygen Species ◽  
Regulated Cell Death ◽  
The Future ◽  
Dependent Form ◽  
Design Ideas ◽  
Emerging Therapy

Ferroptosis, a new iron- and reactive oxygen species–dependent form of regulated cell death, has attracted much attention in the therapy of various types of tumors. With the development of nanomaterials, more and more evidence shows the potential of ferroptosis combined with nanomaterials for cancer therapy. Recently, there has been much effort to develop ferroptosis-inducing nanomedicine, specially combined with the conventional or emerging therapy. Therefore, it is necessary to outline the previous work on ferroptosis-inducing nanomedicine and clarify directions for improvement and application to cancer therapy in the future. In this review, we will comprehensively focus on the strategies of cancer therapy based on ferroptosis-inducing nanomedicine currently, elaborate on the design ideas of synthesis, analyze the advantages and limitations, and finally look forward to the future perspective on the emerging field.

scholarly journals Ferroptosis, radiotherapy, and combination therapeutic strategies

2021 ◽  
Author(s):  
Guang Lei ◽  
Chao Mao ◽  
Yuelong Yan ◽  
Li Zhuang ◽  
Boyi Gan
Keyword(s):  
Cell Death ◽  
Fatty Acid ◽  
Cancer Therapy ◽  
Polyunsaturated Fatty Acid ◽  
Tumor Suppression ◽  
Therapeutic Strategies ◽  
Cellular Membranes ◽  
Regulated Cell Death ◽  
Dependent Form

AbstractFerroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.

scholarly journals Heat stress induces ferroptosis in a photosynthetic prokaryote

2019 ◽  
Author(s):  
Anabella Aguilera ◽  
Federico Berdun ◽  
Carlos Bartoli ◽  
Charlotte Steelheart ◽  
Matías Alegre ◽  
...  
Keyword(s):  
Cell Death ◽  
Heat Stress ◽  
Similar Process ◽  
Cell Death Pathway ◽  
Regulated Cell Death ◽  
Cell Death Program ◽  
Dependent Form ◽  
A Cell ◽  
Eukaryotic Organisms ◽  
Pcc 6803

AbstractFerroptosis is an oxidative iron-dependent form of cell death recently described in eukaryotic organisms like animals, plants and parasites. Here we report that a similar process takes place in the cyanobacterium Synechocystis sp. PCC 6803 in response to heat stress. After a heat shock, Synechocystis cells undergo a cell death pathway that can be suppressed by canonical ferroptosis inhibitors or by external addition of calcium, glutathione or ascorbic acid. Moreover, as described for eukaryotic cells ferroptosis, this pathway is characterized by an early depletion of antioxidants, and by lipid peroxidation. As in general prokaryotes membranes contain poorly oxidizable saturated or monounsaturated lipid molecules, it was thought that they were not susceptible to ferroptosis. Interestingly, cyanobacteria contain thylakoid membranes that are enriched in polyunsaturated-fatty-acid-containing phospholipids, which might explain their sensitivity to ferroptosis. These results indicate that all of the hallmarks described for eukaryotic ferroptosis are conserved in photosynthetic prokaryotes and suggest that ferroptosis might be an ancient cell death program.SummaryAguilera et al, show that ferroptosis, an oxidative and iron-dependent form of regulated cell death, plays an important role in the cyanobacterium Synechocystis sp. PCC 6803 in response to heat stress.

scholarly journals Worms, Fat, and Death: Caenorhabditis elegans Lipid Metabolites Regulate Cell Death

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 125
Author(s):  
Marcos A. Perez ◽  
Jennifer L. Watts
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Model Organism ◽  
Genetic Pathways ◽  
C Elegans ◽  
Regulated Cell Death ◽  
Dietary Polyunsaturated Fatty Acids ◽  
Dependent Form ◽  
Lipid Metabolites ◽  
Regulate Cell Death

Caenorhabditis elegans is well-known as the model organism used to elucidate the genetic pathways underlying the first described form of regulated cell death, apoptosis. Since then, C. elegans investigations have contributed to the further understanding of lipids in apoptosis, especially the roles of phosphatidylserines and phosphatidylinositols. More recently, studies in C. elegans have shown that dietary polyunsaturated fatty acids can induce the non-apoptotic, iron-dependent form of cell death, ferroptosis. In this review, we examine the roles of various lipids in specific aspects of regulated cell death, emphasizing recent work in C. elegans.

C-ferroptosis is an iron-dependent form of regulated cell death in cyanobacteria

2021 ◽  
Vol 221 (2) ◽  
Author(s):  
Anabella Aguilera ◽  
Federico Berdun ◽  
Carlos Bartoli ◽  
Charlotte Steelheart ◽  
Matías Alegre ◽  
...  
Keyword(s):  
Cell Death ◽  
Similar Process ◽  
Cell Death Pathway ◽  
Regulated Cell Death ◽  
Cell Death Program ◽  
Dependent Form ◽  
A Cell ◽  
Eukaryotic Organisms ◽  
Synechocystis Sp ◽  
Pcc 6803

Ferroptosis is an oxidative and iron-dependent form of regulated cell death (RCD) recently described in eukaryotic organisms like animals, plants, and parasites. Here, we report that a similar process takes place in the photosynthetic prokaryote Synechocystis sp. PCC 6803 in response to heat stress. After a heat shock, Synechocystis sp. PCC 6803 cells undergo a cell death pathway that can be suppressed by the canonical ferroptosis inhibitors, CPX, vitamin E, Fer-1, liproxstatin-1, glutathione (GSH), or ascorbic acid (AsA). Moreover, as described for eukaryotic ferroptosis, this pathway is characterized by an early depletion of the antioxidants GSH and AsA, and by lipid peroxidation. These results indicate that all of the hallmarks described for eukaryotic ferroptosis are conserved in photosynthetic prokaryotes and suggest that ferroptosis might be an ancient cell death program.

scholarly journals Targeting Ferroptosis to Treat Cardiovascular Diseases: A New Continent to Be Explored

2021 ◽  
Vol 9 ◽  
Author(s):  
Fangze Huang ◽  
Ronghua Yang ◽  
Zezhou Xiao ◽  
Yu Xie ◽  
Xuefeng Lin ◽  
...  
Keyword(s):  
Cell Death ◽  
Cardiovascular Diseases ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glutamine Metabolism ◽  
Lipid Hydroperoxides ◽  
Genetic Manipulations ◽  
Regulated Cell Death ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Cardiovascular diseases, including cardiomyopathy, myocardial infarction, myocardial ischemia/reperfusion injury, heart failure, vascular injury, stroke, and arrhythmia, are correlated with cardiac and vascular cell death. Ferroptosis is a novel form of non-apoptotic regulated cell death which is characterized by an iron-driven accumulation of lethal lipid hydroperoxides. The initiation and execution of ferroptosis are under the control of several mechanisms, including iron metabolism, glutamine metabolism, and lipid peroxidation. Recently, emerging evidence has demonstrated that ferroptosis can play an essential role in the development of various cardiovascular diseases. Recent researches have shown the ferroptosis inhibitors, iron chelators, genetic manipulations, and antioxidants can alleviate myocardial injury by blocking ferroptosis pathway. In this review, we systematically described the mechanisms of ferroptosis and discussed the role of ferroptosis as a novel therapeutic strategy in the treatment of cardiovascular diseases.

scholarly journals O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Guoqing Zhu ◽  
Abduh Murshed ◽  
Haojie Li ◽  
Ji Ma ◽  
Ni Zhen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Liver Cancer ◽  
Iron Concentration ◽  
Therapeutic Strategies ◽  
Lipid Hydroperoxides ◽  
Regulated Cell Death ◽  
Increased Sensitivity ◽  
Hcc Cells

AbstractFerroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. YAP has been reported to play a pivotal role in controlling ferroptotic death, and the expression of YAP is enhanced and stabilized by O-GlcNAcylation. However, whether O-GlcNAcylation can increase the sensitivity of hepatocellular carcinoma (HCC) cells to ferroptosis remains unknown. In the present study, we found that O-GlcNAcylation increased the sensitivity of HCC cells to ferroptosis via YAP. Moreover, YAP increased the iron concentration in HCC cells through transcriptional elevation of TFRC via its O-GlcNAcylation. With YAP knockdown or YAP-T241 mutation, the increased sensitivity to ferroptosis induced by O-GlcNAcylation was abolished. In addition, the xenograft assay confirmed that O-GlcNAcylation increased ferroptosis sensitivity via TFRC in vivo. In summary, we are the first to find that O-GlcNAcylation can increase ferroptosis sensitivity in HCC cells via YAP/TFRC. Our work will provide a new basis for clinical therapeutic strategies for HCC patients.

scholarly journals Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?

2021 ◽  
Vol 9 ◽  
Author(s):  
Jia-Yue Duan ◽  
Xiao Lin ◽  
Feng Xu ◽  
Su-Kang Shan ◽  
Bei Guo ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Vital Role ◽  
Lipid Hydroperoxides ◽  
Regulated Cell Death ◽  
Metabolic Bone ◽  
Dependent Form ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Ferroptosis is classified as an iron-dependent form of regulated cell death (RCD) attributed to the accumulation of lipid hydroperoxides and redox imbalance. In recent years, accumulating researches have suggested that ferroptosis may play a vital role in the development of diverse metabolic diseases, for example, diabetes and its complications (e.g., diabetic nephropathy, diabetic cardiomyopathy, diabetic myocardial ischemia/reperfusion injury and atherosclerosis [AS]), metabolic bone disease and adrenal injury. However, the specific physiopathological mechanism and precise therapeutic effect is still not clear. In this review, we summarized recent advances about the development of ferroptosis, focused on its potential character as the therapeutic target in metabolic diseases, and put forward our insights on this topic, largely to offer some help to forecast further directions.

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