erastin and Reperfusion-Injury

Cell survival or death is one critical issue in inflammatory responses. Ferroptosis, which is characterized by iron-dependent lethal lipid peroxidation, has been found to participate in the development of cancers, degenerative brain diseases and ischemia-reperfusion injuries. Incorporation of polyunsaturated fatty acids (PUFAs) into cellular membranes represents a vulnerability to invasion of microbials and sterile stimuli. In addition, the competition for iron in the battle between microbials and host cells underlies infection development. Although host cells have been equipped with complex antioxidant systems to combat lethal accumulation of lipid peroxidation, emerging evidence suggests several pathogens may target PUFAs in the cell membrane, and manipulate ferroptosis as a way for pathogen propagation. Moreover, ferroptosis takes part in the progression of sterile inflammations, such as cigarette smoke-induced chronic obstructive pulmonary disease, stroke and ischemia-reperfusion injuries. As iron-dependent oxidative stress and lipid peroxidation are common features for ferroptosis and inflammatory diseases, underlying mechanisms linking such pathological conditions will be discussed in this review. Progress in the research of ferroptosis may shed more light on the etiology and treatment of inflammatory diseases.

Topics: Animals; Atherosclerosis; Ferroptosis; Glutathione; Humans; Infections; Inflammation; Iron; Iron Chelating Agents; Lipid Peroxidation; Lipoxygenases; Membrane Lipids; Oxidative Stress; Piperazines; Reactive Oxygen Species; Reperfusion Injury; Stroke

Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological and morphological features when compared to the other cell death patterns. The loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4), the presence of redox-active iron and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are considered as distinct fingerprints of ferroptosis. Several pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion, p53, Keap1/Nrf2 and phospholipid biosynthesis, can modify susceptibility to ferroptosis. Through the decades, various diseases, including acute kidney injury; cancer; ischemia-reperfusion injury; and cardiovascular, neurodegenerative and hepatic disorders, have been associated with ferroptosis. In this review, we provide a comprehensive analysis of the main biological and biochemical mechanisms of ferroptosis and an overview of chemicals used as inducers and inhibitors. Then, we report the contribution of ferroptosis to the spectrum of liver diseases, acute or chronic. Finally, we discuss the use of ferroptosis as a therapeutic approach against hepatocellular carcinoma, the most common form of primary liver cancer.

Topics: alpha-Tocopherol; Animals; Autophagy; Chemical and Drug Induced Liver Injury; Cyclohexylamines; Cysteine; Ferroptosis; Glutathione; Heme; Humans; Iron; Kelch-Like ECH-Associated Protein 1; Lipid Peroxidation; Lipoxygenase; Liver Diseases; Liver Neoplasms; Oxidative Stress; Phenylenediamines; Phospholipid Hydroperoxide Glutathione Peroxidase; Piperazines; Quinoxalines; Reactive Oxygen Species; Reperfusion Injury; Signal Transduction; Sorafenib; Spiro Compounds; Sulfasalazine; Tumor Suppressor Protein p53

Energy stress depletes ATP and induces cell death. Here we identify an unexpected inhibitory role of energy stress on ferroptosis, a form of regulated cell death induced by iron-dependent lipid peroxidation. We found that ferroptotic cell death and lipid peroxidation can be inhibited by treatments that induce or mimic energy stress. Inactivation of AMP-activated protein kinase (AMPK), a sensor of cellular energy status, largely abolishes the protective effects of energy stress on ferroptosis in vitro and on ferroptosis-associated renal ischaemia-reperfusion injury in vivo. Cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses further link AMPK regulation of ferroptosis to AMPK-mediated phosphorylation of acetyl-CoA carboxylase and polyunsaturated fatty acid biosynthesis. Our study demonstrates that energy stress inhibits ferroptosis partly through AMPK and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy-stress signalling.

Topics: A549 Cells; Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Cell Line, Tumor; Cyclohexylamines; Embryo, Mammalian; Energy Metabolism; Fatty Acids, Unsaturated; Ferroptosis; Fibroblasts; Gene Expression Regulation; Glucose; Humans; Iron; Kidney; Lipid Peroxidation; MCF-7 Cells; Mice; Mice, Transgenic; Phenylenediamines; Phosphorylation; Piperazines; Primary Cell Culture; Pyrazoles; Pyrimidines; Reperfusion Injury; Signal Transduction; Stress, Physiological