Ferroptosis in Health and Disease 2nd Edition

This updated and expanded volume gives new insights on ferroptosis – an iron-dependent form of non-apoptotic cell death. The collection of chapters discusses the two major pathways through which ferroptosis can occur: the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Readers will gain an understanding of the multiple levels, on which this special cell death is regulated. Hence, the contributions will take a closer look at epigenetic, transcriptional, posttranscriptional and posttranslational layers. Among the described regulators and transcription factors are GPX4, ACSL4 and NFE2L2. This edited volume collects reviews related to current knowledge on the integrated molecular machinery of ferroptosis, thereby also describing how dysregulated ferroptosis is involved in human diseases. Preface Contents 1: Lipid Metabolism and Homeostasis in Ferroptosis 1.1 Introduction 1.2 Lipid Resource 1.3 Lipid Synthesis 1.3.1 The ACSL4-LPCAT3-PUFA-PE Pathway 1.3.2 The ACSL4-SOAT1-PUFA-CE Pathway 1.3.3 The Peroxisomes-PUFA-PL Pathway 1.3.4 The SREBP1-SCD Pathway 1.4 Lipid Peroxidation 1.5 Lipid Storage and Degradation 1.6 Lipid Uptake and Utilization 1.7 Defense Mechanism 1.7.1 GPX4 1.7.2 AIFM2 1.7.3 DHODH 1.7.4 MGST1 1.7.5 ALDH1B1 1.7.6 NFE2L2 1.7.7 NUPR1 1.7.8 ESCRT-III 1.8 Conclusion and Outlook References 2: Iron Metabolism and Ferroptosis 2.1 Introduction 2.2 Iron Metabolism in Circulation 2.3 Iron Metabolism in Cells 2.4 Excess Iron and Cancer 2.5 Ferroptosis in Iron Excess 2.6 Ferroptosis and Ferritinophagy 2.7 Conclusion References 3: Targeting Epigenetic Regulation of Ferroptosis in Cancer Therapy 3.1 Background 3.2 Mechanisms and Regulators of Ferroptosis 3.3 Epigenetic Regulation in Ferroptosis 3.3.1 Chromatin Remodeling 3.3.2 DNA Methylation 3.3.3 Histones Modification 3.3.4 Non-coding RNAs 3.3.5 Other Epigenetic Regulators 3.4 Epigenetic Drugs in Cancer Therapy 3.5 Conclusions and Perspectives References 4: The Role of Autophagy in Ferroptosis 4.1 Introduction 4.2 Mechanism of Autophagy 4.2.1 Phagophore 4.2.2 Autophagosome 4.2.3 Autolysosome 4.3 Selective Autophagy 4.4 Mechanism of Ferroptosis 4.4.1 Iron Toxicity 4.4.2 Lipid Toxicity 4.4.3 GPX4 Antioxidant System 4.4.4 AIFM2 Antioxidant System 4.4.5 DHODH Antioxidant System 4.4.6 NFE2L2 Antioxidant System 4.4.7 Membrane Repair System 4.5 Autophagy in Ferroptosis 4.5.1 Ferritinophagy 4.5.2 Lipophagy 4.5.3 Clockophagy 4.5.4 Mitophagy 4.5.5 Reticulophagy 4.5.6 GPX4 Degradation 4.5.7 CDH2 Degradation 4.5.8 SLC40A1 Degradation 4.5.9 BECN1-Mediated System xc- Inhibition 4.5.10 Lysosomal Membrane Permeabilization 4.6 Conclusions and Perspectives References 5: Heat Shock Proteins and HSF1 in Ferroptosis 5.1 Introduction 5.2 HSPs in Protein Homeostasis 5.2.1 Heat Shock Response 5.2.2 Unfolded Protein Response 5.2.3 Mitochondrial Unfolded Protein Response 5.3 Mechanism of Ferroptosis 5.3.1 Antioxidant Pathways 5.3.2 Iron Overload 5.3.3 Lipid Peroxidation 5.3.4 Membrane Damage and Repair 5.4 The Function of HSPs in Ferroptosis 5.4.1 Small HSPs in Ferroptosis 5.4.2 HPS40 in Ferroptosis 5.4.3 HSP60 in Ferroptosis 5.4.4 HSP70 in Ferroptosis 5.4.5 HSP90 in Ferroptosis 5.4.6 Ubiquitin in Ferroptosis 5.4.7 HSF1 in Ferroptosis 5.5 Conclusions and Perspectives References 6: The Ongoing Search for a Biomarker of Ferroptosis 6.1 Definition and Regulation of Ferroptosis 6.2 Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) 6.2.1 The Role of ACSL4 in Ferroptosis 6.2.2 ACSL4 as a Biomarker of Pathophysiological Ferroptosis 6.3 Transferrin Receptor 1 (TfR1) 6.3.1 The Role of TfR1 in Ferroptosis 6.3.2 TfR1 as Biomarker of Ferroptosis 6.4 Lipid Peroxidation-Associated Protein Adducts 6.4.1 Accumulation of Lipid Peroxidation By-products during Ferroptosis 6.4.2 4-HNE Protein Adducts as Biomarkers of Ferroptosis 6.5 Innovative Approaches 6.6 Conclusion References 7: p53 and Ferroptosis 7.1 Introduction 7.1.1 Ferroptosis Basics 7.2 p53 as a pro-Ferroptosis Regulator 7.2.1 Transcriptional Suppression of SLC7A11 7.2.2 Transcriptional Activation of SAT1 7.2.3 Transcriptional Activation of GLS2 7.2.4 Mitochondrial Translocation and Interaction with SLC25A28 7.3 p53 as an Anti-Ferroptosis Regulator 7.3.1 Transcriptional Activation of CDKN1A/p21 7.3.2 Posttranslational Inhibition of DPP4 Activity 7.3.3 Transcriptional Activation of iPLA2beta 7.4 Conclusion References 8: Ferroptosis in Cardiovascular Disease 8.1 Introduction 8.2 Iron in the Heart 8.2.1 The Physiological Role of Iron in the Heart 8.2.2 The Pathological Role of Excess Iron in the Heart 8.2.3 The Effects of Iron Homeostasis on Cell Function 8.3 Ferroptosis and Reactive Oxygen Species (ROS) Production 8.3.1 Iron Homeostasis and ROS Generation 8.3.2 Glutathione Peroxidase 4 (GPX4) 8.3.3 Ferroptosis Suppressor Protein 1 (FSP1) 8.3.4 Mitochondria and Dihydroorotate Dehydrogenase (DHODH) 8.3.5 Lipid Peroxidation 8.4 Pathological Features of Ferroptosis in the Heart 8.4.1 Ferroptosis in Ischemia-Reperfusion (I/R) Injury 8.4.2 Ferroptosis in Cardiomyopathy 8.4.2.1 Iron Overload and LV Remodeling 8.4.3 Diabetic Cardiomyopathy 8.4.4 Chemical-Induced cardiomyopathy 8.5 Potential Therapies Targeting Ferroptosis in Cardiovascular Disease 8.5.1 Regulation of Iron in the Labile Iron Pool 8.5.2 Iron Storage and Transport 8.5.3 Iron Chelation 8.5.4 ROS Inhibition 8.5.5 Glutathione (GSH) and Glutathione Peroxidase 4 (Gpx4) Activity 8.5.6 Nrf2-Mediated Antioxidant Activity 8.5.7 GPX4-Independent Antioxidants 8.5.8 Ferrostatin-1 and Other Small Molecule Inhibitors of Ferroptosis 8.5.9 Lipid Metabolism and Membrane Integrity 8.5.10 Inhibition of Inflammation 8.6 Conclusions References 9: Understanding Ferroptosis from a Free Radical Perspective 9.1 Introduction 9.2 Lipid Peroxidation Reaction in Ferroptosis 9.2.1 Radical Chain Reactions Responsible for Lipid Peroxidation 9.2.2 Roles of Free Iron in Ferroptosis 9.2.3 Cys-GSH-GPX4 Axis as a Primary Defense System against Ferroptosis 9.2.4 Regulators of Phospholipid Peroxidation 9.3 Ferroptosis Occurs Preferentially in Metabolically Active Cells 9.3.1 Association of Ferroptosis with Active Metabolic State 9.3.2 Mitochondria as a Source for Radicals 9.3.3 Sources of Free Iron in Mitochondrial 9.4 Future Mission of Ferroptosis Research 9.4.1 Approach to Detect Ferroptotic Cells In Situ 9.4.2 Prevention and Treatment of Ferroptosis-related Diseases References 10: The NRF2-anti-ferroptosis Axis in Health and Disease 10.1 Introduction 10.2 A Brief History of Ferroptosis 10.3 The NRF2 Pathway and Its Relevance to Ferroptosis 10.4 NRF2 Regulation of Ferroptosis 10.4.1 Lipid Peroxidation 10.4.2 Iron Metabolism and Homeostasis 10.5 NRF2 and Ferroptosis in Disease 10.5.1 Cancer 10.5.2 Neurodegeneration 10.5.3 Diabetes 10.5.4 Liver Disease 10.5.4.1 NAFLD/NASH 10.5.4.2 Liver Fibrosis 10.6 Acute Organ Injury 10.7 Conclusions and Future Perspectives References 11: Epigenetic Modification in Ferroptosis 11.1 Introduction 11.2 Molecular Mechanisms of Ferroptosis 11.3 Molecular Mechanisms of Epigenetic Modification 11.4 Association Between Epigenetics and Ferroptosis 11.4.1 DNA Modification 11.4.2 RNA Modifications 11.4.2.1 m6A 11.4.2.2 m5C 11.4.2.3 Other RNA Modifications ncRNAs 11.5 Chromatin Remodeling Factors 11.6 Histone Modifications 11.7 Non-histone Modifications 11.8 Selenium 11.9 Conclusion References 12: Organelle-specific Mechanisms of Ferroptosis 12.1 Introduction 12.2 Role of Mitochondria in Ferroptosis 12.2.1 Morphological Morphology in Ferroptosis 12.2.2 Mitochondrial VDACs as Targets for Erastin 12.2.3 Mitochondrial ROS 12.2.4 Mitochondrial Tricarboxylic Acid Cycle and Oxidative Phosphorylation 12.2.5 Mitochondrial Iron 12.2.6 Mitochondrial DNA 12.2.7 Mitochondrial Proteases 12.2.8 Mitophagy and Ferroptosis 12.2.9 Mitochondrial Crosstalk between Ferroptosis and Apoptosis 12.3 Role of Lipid Droplets (LDs) in Ferroptosis 12.4 Role of Endoplasmic Reticulum (ER) in Ferroptosis 12.4.1 Lipid Peroxidation in ER 12.4.2 ER Stress 12.4.3 ER-resident Proteins 12.4.4 ER-phagy 12.5 Role of Lysosomes in Ferroptosis 12.5.1 Lysosomal Cathepsins 12.5.2 Lysosomal Iron and ROS 12.5.3 Lysosomal Nitric Oxide 12.5.4 Lysosome in Autophagy 12.6 Role of Ribosome in Ferroptosis 12.7 Role of Peroxisomes in Ferroptosis 12.8 Role of Golgi in Ferroptosis 12.9 Conclusions and Perspectives References 13: Ferroptosis: A Promising Therapeutic Target for Cardiovascular Diseases 13.1 Introduction 13.2 Role and Signaling Pathways of Ferroptosis in CVD and Potential Therapeutic Targets 13.2.1 Myocardial Infarction and Heart Ischemia 13.2.2 Cardiomyopathy 13.2.3 Cardiotoxicity 13.2.4 Cardiac Remodeling and Hypertrophy 13.2.5 Atherosclerosis 13.2.6 Heart Failure 13.3 Concluding Remarks and Therapeutic Directions References 14: Ferroptosis in Central Nervous System Hypoxia-Ischemia 14.1 Introduction 14.1.1 Triggers of Ferroptosis 14.1.2 Suppressors of Ferroptosis 14.2 Ferroptosis in Non-HI Brain Disorders 14.3 Ferroptosis after HIBI 14.3.1 HIBI Pathophysiology 14.3.2 ROS Generation after HIBI 14.3.3 ACSL4- and LOX-Mediated Lipid Peroxidation after HIBI 14.3.4 Iron Accumulation after HIBI 14.3.5 Antioxidants and Ferroptosis after HIBI 14.3.6 Inflammation and Ferroptosis after HIBI 14.4 Pharmacological Inhibition of Ferroptosis after HIBI 14.5 Conclusions References 15: Involvement of Ferroptosis in Lupus Nephritis 15.1 Introduction 15.2 Glomerular and Tubular Injury in LN 15.2.1 Glomerular Injury in LN 15.2.2 Tubular Injury in LN 15.2.3 Involvement of Oxidative Stress in Tubular Injury in LN 15.3 Role of Iron in LN 15.3.1 Iron in the Physiological Condition 15.3.2 Iron in Pathological Condition 15.4 Role of Ferroptosis in LN 15.4.1 Ferroptosis 15.4.2 Involvement of Iron in Ferroptosis 15.4.3 Involvement of ROS in Ferroptosis 15.5 Biomarkers in LN 15.5.1 Current Biomarkers in LN 15.5.2 Future Biomarkers in LN 15.6 Perspective in LN References 16: Ferroptosis and Infectious Diseases 16.1 Introduction 16.2 The Hallmarks of Ferroptosis 16.3 Induction and Inhibitions of Ferroptosis 16.4 Iron Metabolism 16.5 Lipid Peroxides and Lipid Peroxidation 16.6 Ferroptosis and Infectious Diseases 16.7 Bacterial Infections 16.7.1 Mycobacterial tuberculosis (Mtb) 16.7.2 Pseudomonas aeruginosa 16.7.3 Salmonella 16.7.4 Chlamydia trachomatis 16.7.5 Polymicrobial-Induced Sepsis 16.8 Viral Infections 16.8.1 Lymphocytic Choriomeningitis 16.8.2 Epstein-Barr Virus 16.9 Enterovirus and Coronaviruses 16.9.1 Human Immunodeficiency Virus 16.9.2 Hepatitis Virus 16.9.3 Other Viruses 16.10 Parasite Infections 16.10.1 Plasmodium 16.10.2 Leishmania Major 16.10.3 Fungi 16.11 Conclusion and Perspectives References 17: Selenium Metabolic Pathway in Ferroptotic Cell Death 17.1 Introduction 17.2 Ferroptosis 17.3 Characteristics of Ferroptosis 17.4 Role of Selenium in Ferroptosis Pathway 17.5 Ferroptosis-Induced ER Stress 17.6 p62/Keap1/NRF2 Axis Protects against Ferroptosis 17.7 BRF2 Selenoprotein: Cancer Cell 17.8 Protein Synthesis 17.9 Selenoprotein ́s Regulation of Multiple Transcription Factors 17.10 Conclusion References 18: Epigenetic and Posttranslational Regulation of Ferroptosis 18.1 Introduction 18.2 Epigenetic Regulation of Ferroptosis Modulators 18.2.1 Chromatin Remodeling 18.2.2 Histone Modification 18.2.2.1 Histone Ubiquitination 18.2.2.2 Histone Methylation 18.2.2.3 Histone beta-hydroxybutyrylation 18.2.3 DNA Methylation 18.3 mRNA Modification 18.3.1 N6-methyladenosine 18.3.2 N4-acetylcytidine 18.4 Posttranslational Regulation of Ferroptosis Regulators 18.4.1 Phosphorylation 18.4.2 Ubiquitination 18.4.3 UFMylation 18.4.4 Alkylation 18.4.5 Succination 18.4.6 Myristoylation 18.5 Conclusion References 19: Phospholipid Peroxidation in Health and Disease 19.1 Introduction 19.2 Oxidation Process of Phospholipids 19.3 Reduction and Remodeling Process of Phospholipids 19.4 Detection Methods of Phospholipid Peroxidation 19.4.1 Fluorescent Probes 19.4.2 Chemiluminescence Assay and Immunoassay for Detecting Phospholipid Peroxidation Products 19.4.3 Oxidative Lipidomic Based on LC-MS 19.5 The Role of Phospholipid Peroxidation in Cellular Signal Transduction 19.5.1 The Role of Phospholipid Peroxidation in Driving Ferroptosis 19.5.2 The Role of Phospholipid Peroxidation in the Autophagy Inhibition 19.5.3 The Role of Phospholipid Peroxidation in Phagocytic Signaling 19.5.4 The Role of Protein Modification byPhospholipid Peroxidation Products in Signal TransductionRegulation 19.6 Phospholipid Peroxidation and Diseases 19.6.1 Neurodegenerative Diseases 19.6.1.1 Alzheimer ́s Disease (AD) 19.6.1.2 Parkinson ́s Disease (PD) 19.6.1.3 Amyotrophic Lateral Sclerosis (ALS) 19.6.1.4 Multiple Sclerosis (MS) 19.6.2 Immune Function and Tumor 19.7 Conclusion References 20: PKCβII-ACSL4 Axis Triggers Ferroptosis and Its Potential Implication in Ferroptosis-Related Diseases References 21: Cancer Treatment with Ferroptosis by a Combination of Iron Nanoparticles and Gene Therapy 21.1 Introduction 21.2 IONs-Induced Ferroptosis for Cancer 21.2.1 IONs Therapy 21.2.2 Challenges of IONs Therapy 21.3 Gene Therapy-Induced Ferroptosis for Cancer 21.3.1 Gene Therapy 21.3.2 Gene Therapy-Induced Ferroptosis for Cancer 21.4 IONs and Gene Therapy Co-Induced Ferroptosis for Cancer 21.4.1 GIFT Strategy 21.4.2 FAST Strategy 21.4.3 Advantages of FAST 21.5 Conclusions and Perspectives References 22: Inhibitors of Oxytosis/Ferroptosis: A New Class of Therapeutics for Alzheimer ́s Disease 22.1 Introduction 22.2 The Dire Situation with the AD Therapeutics Available 22.3 Oxytosis/Ferroptosis in AD, a Therapeutic Target Worth Pursuing 22.4 Drug Discovery to Develop Inhibitors of Oxytosis/Ferroptosis 22.5 Preclinical Studies 22.6 The Clinical Testing Path, Challenges, and Hope 22.7 Biomarkers 22.8 Discussion and Conclusion References