Ferroptosis: Mechanism and Diseases (Advances in Experimental Medicine and Biology, 1301)

This book focuses on the emerging role of ferroptosis in human diseases. It gives a detailed perspective on how to induce or suppress ferroptosis to treat challenging conditions such as infectious diseases, including COVID-19, tuberculosis, parasitic diseases and cancer. The book serves as a practical guide by providing a valuable collection of all currently known activators or inhibitors of ferroptosis. It will enable readers to choose molecules for experimental design for in vitro and in vivo studies of ferroptosis. Furthermore, this volume highlights the aspects of iron metabolism and its connection to ferritinophagy, a ferritin selective autophagy, with profound implications in neurodegenerative diseases such as Alzheimer, Parkinson, Huntington and ALS. Lastly, it describes necroptosis, another important form of cell death, along with its connections to human disorders and potential crosstalk with ferroptosis. While covering basic concepts, the book delvesinto mechanisms and modulation of ferroptosis for treating a wide variety of human diseases thus offering a valuable and informative resource for both, scientists and clinical researchers. Foreword Contents About the Editors 1: Ferroptosis: Concepts and Definitions References 2: Overcoming Therapeutic Challenges for Pancreatic Ductal Adenocarcinoma with xCT Inhibitors 2.1 Pancreatic Cancer Therapeutic Challenges 2.2 Ferroptosis and PDAC 2.2.1 xCT-Based Ferroptosis Inducers as Systemic Therapeutics for PDAC 2.2.2 xCT-Based Early Detection of Metastasized PDAC 2.3 Metabolic Status Dictates Sensitivity Toward Ferroptosis 2.4 Promoting Ferroptosis and Antigenicity in PDAC 2.5 How Stromal Compartment Influences Sensitivity to Ferroptosis 2.6 Concluding Remarks References 3: Iron Homeostasis and Metabolism: Two Sides of a Coin 3.1 Iron in Physiology and Disease 3.1.1 Iron: Origin, Chemical Properties and Evolution 3.1.2 Insights into the Redox Chemistry of Iron 3.1.3 Strategies for Iron Assimilation and Transport 3.2 Concluding Remarks References 4: The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis 4.1 Introduction 4.2 NCOA4-Mediated Ferritinophagy 4.3 NCOA4-Mediated Ferritinophagy and Ferroptosis 4.4 Ferritinophagy and Ferroptosis in Cancer 4.5 Ferritinophagy and Ferroptosis in Neurodegeneration 4.5.1 Neuroferritinopathy 4.5.2 Alzheimer’s Disease 4.5.3 Parkinson’s Disease 4.5.4 Huntington’s Disease 4.5.5 Amyotrophic Lateral Sclerosis 4.5.6 Brain Injury 4.6 Conclusions and Future Directions References 5: Emerging Role for Ferroptosis in Infectious Diseases 5.1 Introduction 5.2 Necrosis in Infectious Diseases 5.2.1 Pyroptosis and Necroptosis in Infectious Diseases 5.3 Ferroptosis in Infectious Diseases 5.3.1 Pathogen-Induced Ferroptotic Cell Death 5.3.1.1 Bacterial Infections Salmonella Typhimurium Infection Mycobacterium tuberculosis Infection Pseudomonas aeruginosa Infection Polymicrobial Sepsis 5.3.1.2 Viral Infection 5.3.1.3 Parasitic Infection 5.4 Concluding Remarks References 6: Small Molecule Regulators of Ferroptosis 6.1 Introduction 6.2 Activators of Ferroptosis 6.2.1 Targeting GPX4 Activity and Lipid Production 6.2.1.1 Deficiency of GPX4 Production (Scheme 6.1; Fig. 6.2) 6.2.1.2 Boost of Lipid Production (Scheme 6.1; Fig. 6.3) 6.2.2 GSH Depletion and Nuclear Factor (Erythroid-Derived 2)-like 2 (NrF2) Inhibition 6.2.2.1 System Xc- Inhibition (Scheme 6.1; Fig. 6.4) 6.2.2.2 Alteration of GSH Metabolism (Scheme 6.1; Fig. 6.5) 6.2.2.3 NrF2 Inhibition (Scheme 6.1; Fig. 6.6) 6.2.3 Iron and ROS Production 6.2.3.1 Labile iron Pool Enrichment (Scheme 6.2; Fig. 6.7) 6.2.3.2 Inducing ROS (Scheme 6.2; Fig. 6.9) 6.2.3.3 A Small molecule Inducer of Membrane Leakage (Scheme 6.2; Fig. 6.10) 6.3 Inhibitors of Ferroptosis 6.3.1 Lipoxygenases (LOXs), Lipid peroxidation and Lipid Production 6.3.1.1 Arachidonate 5-Lipoxygenase Inhibitors (Scheme 6.1; Fig. 6.11) 6.3.1.2 Arachidonate 15-Lipoxygenase Inhibitor (Scheme 6.1; Fig. 6.12) 6.3.1.3 Unspecified Lipoxygenase Inhibitors (Scheme 6.1; Fig. 6.13) 6.3.1.4 Lipid peroxidation Blockers – Selenium-Based Compounds Mimic GPX4 Activity and Stabilize GPX4 (Scheme 6.1; Fig. 6.14) 6.3.1.5 Lipid peroxidation Blockers – Inhibition of Propagation of Free Radicals (Scheme 6.2; Fig. 6.15) 6.3.1.6 Lipid Production Blockers (Scheme 6.1; Fig. 6.16) 6.3.2 Iron and ROS Production 6.3.2.1 Decreasing the Labile iron Pool (Scheme 6.2; Fig. 6.17) 6.3.2.2 NOXs-Related Inhibitors (Scheme 6.1; Fig. 6.18) 6.3.3 Increasing GSH and Modulating MAPK Expression 6.3.3.1 By-Pass of System Xc− Inhibition (Scheme 6.1; Fig. 6.19) 6.3.3.2 Inhibitors of MAPK-Related Pathway Activation (Fig. 6.20) 6.3.4 Miscellaneous (Fig. 6.21) 6.4 Conclusion References 7: Necroptosis, the Other Main Caspase-Independent Cell Death 7.1 A Brief History of Necroptosis 7.2 Molecular Mechanisms of Necroptosis 7.3 Differences and Similarities Between Necroptosis and Ferroptosis 7.4 Role of necroptosis in Human Diseases 7.4.1 Viral Infection 7.4.2 Cancer 7.4.3 Inflammatory Diseases 7.5 Concluding Remarks References Index This book focuses on the emerging role of ferroptosis in human diseases. It gives a detailed perspective on how to induce or suppress ferroptosis to treat challenging conditions such as infectious diseases, including COVID-19, tuberculosis, parasitic diseases and cancer. The book serves as a practical guide by providing a valuable collection of all currently known activators or inhibitors of ferroptosis. It will enable readers to choose molecules for experimental design for in vitro and in vivo studies of ferroptosis. Furthermore, this volume highlights the aspects of iron metabolism and its connection to ferritinophagy, a ferritin selective autophagy, with profound implications in neurodegenerative diseases such as Alzheimer, Parkinson, Huntington and ALS. Lastly, it describes necroptosis, another important form of cell death, along with its connections to human disorders and potential crosstalk with ferroptosis. While covering basic concepts, the book delves into mechanisms and modulation of ferroptosis for treating a wide variety of human diseases thus offering a valuable and informative resource for both, scientists and clinical researchers.