Aug 23, 2016 ferroptosis is a regulated form of cell death induced by loss of glutathione peroxidase 4 gpx4 phospholipid peroxidase activity and lethal accumulation of reactive oxygen species. Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process. Crosstalk between ferroptosis and apoptosis molecular cancer. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for. Iron toxicity, lipid peroxidation and ferroptosis after. Mar 19, 2019 inhibition of gpx4 function leads to lipid peroxidation and can result in the induction of ferroptosis, an iron.
Dubbing ferroptosis in cancer cells cancer research. Mesh1 is a cytosolic nadph phosphatase that regulates. Resolving the role of lipoxygenases in the initiation and. Ferroptosis is an irondependent and peroxidationdriven form of cell death that is distinct from apoptosis, necrosis and other types of cell death in terms of morphology, genetics, metabolism and molecular biology 2,510. Since the current definition of ferroptosis is a cell death process involving lipid peroxidation that is suppressed by both iron chelators and lipophilic antioxidants, any lethal irondependent lipid peroxidation.
Loss of gpx4 activity and subsequent accumulation of lipid hydroperoxides executes ferroptosis. Ferroptosis is initiated by the failure of the glutathione dependent antioxidant defenses, resulting in unchecked. Moreover, we found that small molecules activating ferroptosis through system x c. Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 gpx4 and. Ferroptosis is an irondependent oxidative form of cell death associated with increased lipid peroxidation and in sufficient capacity to eliminate lipid peroxides. Aug 24, 2017 ferroptosis is a cell death program that is distinct from apoptosis and necroptosis. We have also found evidence that ferroptosis is involved in numerous degenerative diseases and can be. Stockwell1,2,3, ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 gpx4 and subsequent accumulation of lipidbased reactive oxygen species ros, particularly lipid hydroperoxides. Iron chelator inhibits apapinduced hepatotoxicity and lipid peroxidation. Alzheimers disease is a neurodegenerative disease characatarized by lipid peroxidation. This article is published with open access at abstract ferroptosis is a nonapoptotic form of cell death that can be triggered by small molecules or condi. Ferroptosis is an irondependent oxidative form of cell death associated with increased lipid peroxidation and insufficient capacity to eliminate lipid peroxides. Gpx4 at the crossroads of lipid homeostasis and ferroptosis. Differentfromapoptosis and necroptosis, activation of caspase and receptorinteracting protein kinase is not required for induction of ferroptosis 1.
Diffuse large b cell lymphomas and renal cell carcinomas are particularly susceptible to gpx4regulated ferroptosis. Still lacking are convincing proofs that lipoxygenases are involved in. In 2003, a small molecule compound termed erastin was identified, which selectively induced nonapoptotic cell death in both an st and rasg12vdependent manner. The basic mechanism of ferroptosis, therefore, fits the features of activation of lipid peroxidation. Fer1 acts as a lipid ros scavenger and prevents ferroptosis induced by erastin and rsl3 but does not suppress cell death induced by staurosporine an apoptosis inducer or hydrogen peroxide. Modeling the effects of lipid peroxidation during ferroptosis. Ferroptosis is a regulated, nonapoptotic form of cell death distinct from other cell death modalities. In 2012, my lab reported that a novel small molecule named erastin activates a form of nonapoptotic cell death that we termed ferroptosis. Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 gpx4 and subsequent accumulation of lipid based reactive oxygen species ros, particularly lipid hydroperoxides. Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid hydroperoxides. There has been significant research on the pathways leading to the accumulation of oxidized. Gpx4 normally removes the dangerous products of irondependent lipid peroxidation, protecting cell membranes from this type of. Ferroptosis is a recently recognized form of programmed cell death that is dependent on iron and characterized by the accu mulation of lipid peroxidation through. Recent works have identified several regulatory factors of erastin and rsl3induced ferroptosis.
Ferroptosis, implicated in several diseases, is a new form of programmed and nonapoptotic cell death triggered by irondependent lipid peroxidation after inactivation of the cystineglutamate. Smallmolecule inhibitors of gpx4 induce ferroptosis. Studies have linked this form of cell death with a role in suppressing tumorigenesis within the. Gpx4 uses glutathione to eliminate lipid peroxides formed in phospholipids. Finally, it is still unknown exactly why and how lipid peroxidation leads to the death of cells in ferroptosis, and this is a key area of future research see outstanding questions. Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis. Radiationinduced lipid peroxidation triggers ferroptosis and. Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of dna repair and inhibition of apoptosis. Ferroptosis mainly involves genetic changes in iron homeostasis and lipid peroxidation metabolism, but the specific regulatory mechanism needs. Ferroptosis is a form of cell death that requires phospholipid peroxidation and has attracted increased attention, both as a means to eradicate tumors resistant to standard chemotherapy and for its potential contribution to tissue damage such as in ischemiareperfusion.
Regulation of lipid peroxidation and ferroptosis in diverse species. The discovery of ferroptosis partially elucidates the ironrelated cell death. Lipid oxidation requires both the incorporation of polyunsaturated fatty acids pufas into membrane phospholipids pls as well as the import of iron into the cell. Ferroptosis is a distinct form of irondependent cell death 5 that is triggered by oxidative stresses and characterized by the accumulation of lipid peroxidation products 14. Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 gpx4 and subsequent accumulation. Ferroptosis is a nonapoptotic form of cell death resulting from irondependent lipoxygenase enzyme peroxidation of polyunsaturated fatty acids in cell membranes dixon, 2017. Ferroptosis is a form of regulated cell death identi. Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 gpx4. Autophagy promotes ferroptosis by degradation of ferritin. Ferroptosis is an irondependent and peroxidation driven form of cell death that is inhibited by the chelation of iron. Energystressmediated ampk activation inhibits ferroptosis.
Structure, function, and modulation page 1 ferroptosis inducers page 3 lipid peroxidation page 7 ferroptosis inhibitors page 5 oxytosis vs. Ferroptosis is a recently recognized form of cell death caused by accumulation of lipid peroxides. Inhibition of ferroptosis is beneficial in several in vivo and in vitro ich conditions. T cell lipid peroxidation induces ferroptosis and prevents. Reactive oxygen species ros induced lipid peroxidation plays a critical role in cell death including apoptosis, autophagy, and ferroptosis. This led in turn to the identification of lipoxygenases and phkg2 as regulators of pufa peroxidation during ferroptosis. In our established gpx4deficient mef cells, depletion of gpx4 induce iron and 15loxindependent lipid peroxidation at 26 h and caspaseindependent cell death at 72 h, whereas erastin and rsl3 treatment resulted in irondependent ferroptosis by 12 h. Lipid peroxidation is a hallmark of ferroptosis, and emerging form of regulated cell death. The role of ferroptosis in various pathophysiological settings has been evaluated using ferrostatin1 fer1, a smallmolecule inhibitor of ferroptosis. It was initially caught when seeking small molecular compounds for targeting ras mutations, an oncogene. At present, mechanisms that could predict sensitivity andor resistance and that may be.
Mar 26, 2018 ferroptosis is a form of regulated cell death characterized by the accumulation of lipid hydroperoxides. Death by lipid peroxidation wan seok yang1,4, and brent r. This form of irondependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. It is therefore of great interest to understand how ros is produced and eliminated and how rosinduced lipid peroxidation contributes to cell death. Ferroptosis induction may underlie spontaneous human diseases, such as major neurodegeneration and neuroinflammation, causing an excessive cell death. Finally, we have defined biomarkers that predict sensitivity and resistance to ferroptosis, opening the possibility of precision medicines that induce ferroptosis for treating a variety of cancers. The process is driven by the irondependent oxidative degeneration of lipids. Acsl4 dictates ferroptosis sensitivity by shaping cellular. Ferroptosis is caused by loss of activity of the key enzyme that is tasked with repairing oxidative damage to cell membranesglutathione peroxidase 4 gpx4. The center stage taken by phospholipid peroxidation in ferroptosis is highlighted by recent discoveries that demonstrate an. Loss of gpx4 activity and subsequent accumulation of lipid.
This cell death is dependent on free intracellular iron, which is required for the accumulation of toxic lipid ros yang et al. Significance ferroptosis is a regulated form of cell death induced by loss of. Ferroptosis can be prevented by treatment with iron chelator or interference. There has been significant research on the pathways leading to the accumulation of. Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 gpx4 and subsequent accumulation of lipidbased reactive oxygen. Oct, 2019 recently, ferroptosis, a new form of programmed cell death, has been found to be caused by lipid peroxidation, which highlights lipid peroxidation during the physiological process of cell death. Ferroptosis is a regulated form of cell death driven by accumulation of lipid based reactive oxygen species ros dixon et al. Introduction lipid peroxidation has long been implicated in a staggering array of human pathologies. Emerging mechanisms and disease relevance of ferroptosis.
However, the cell death patterns have not been particularly explored. Peroxidation of polyunsaturated fatty acids by lipoxygenases. Lipid peroxidationdependent cell death regulated by gpx4 and. Ferroptosis is a form of rcd driven by irondependent lipid peroxidation. Although ferroptosis is a recently described form of regulated cell death driven by lipid peroxidation, the impact of lipid droplets on ferroptosis remains unidentified. Stockwell1,2,3, ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 gpx4 and subsequent accumulation of lipid based reactive oxygen species ros, particularly lipid hydroperoxides. Ferroptosis is a cell death process driven by damage to cell membranes and linked to numerous human diseases. This form of irondependent cell death is genetically. Promotion of ferroptosis by becn1 is ptdins3kindependent we previously demonstrated that ferroptosis is a process of autophagic cell death, which requires atg5 autophagy related 5. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. Hspa5 regulates ferroptotic cell death in cancer cells.
Ferroptosis, a novel form of regulated cell death, is characterized by a production of reactive oxygen species from accumulated iron and lipid peroxidation. Reactive oxygen speciesinduced lipid peroxidation in. Mechanisms of ferroptosis jennifer yinuo cao1 scott j. Feb 26, 2019 ferroptosis is a form of programmed cell death, distinct from apoptosis, that was identified in 2012.
Lipid peroxides can be synthesized in many contexts and are mediators of disease and death. In this issue of cancer research, liu and colleagues demonstrate that the deubiquitinase dub otub1 is frequently overexpressed in human cancers, and functions to dub trim the ferroptosis process in cancer. The epigenetic regulators and metabolic changes in. Iron overload can induce ros production, oxidation of the lipid, protein and dna, and trigger or mediate cell death. Intracerebral haemorrhage ich accounts for 10%15% of all strokes. The development of the concept of ferroptosis columbia university. This fundamental and conserved mechanism is based on an excess of ros which attacks biomembranes, propagates lipid peroxidation chain reactions, and subsequently induces different types of cell death. It is a devastating event that causes high mortality and morbidity, but it currently lacks effective therapies. This is a pdf file of an unedited manuscript that has. We know that accumulation of oxidized phospholipids is a death signal, but we do not know how this causes cell death and whether it is possible to intervene in. Ferroptosis, a form of irondependent, nonapoptotic cell death that is induced by excessive lipid peroxidation, has been recently identified as a new tumor suppression mechanism. Interestingly, our results indicated that inhibition of erk12 activation by blockade of mek12 also prevented gpx4deficient t cell death in culture, implicating deregulated erk activation caused by lipid peroxidation and further strengthening the idea that gpx4deficient t cells undergo ferroptosis, erastin has been reported to inhibit the x.
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