Ferroptosis

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	The mechanism of ferroptosis

Ferroptosis can be triggered by structurally diverse small molecules (e.g., erastin, sulfasalazine and RSL3). According to morphological, biochemical and genetic characteristics, ferroptosis differs from apoptosis , autophagy and other forms of programmed necrosis. It is characterized by morphological changes such as a reduced size of mitochondria with condensed dense inner membranes , a decrease and even disappearance of mitochondrial cristae , as well as ruptures of the ^[3] . Ferroptosis can be prevented with lipophilic antioxidants , for example and vitamin E , as well as iron chelates such as , but not well-known small molecules that inhibit apoptosis, necrosis and autophagy; for this reason, ferroptosis is isolated as a separate form of cell death ^[1] .

Erastin blocks the X _C −Cys / Glu antiporter , which exchanges extracellular L- cystine for intracellular L- glutamate . Extracellular iron metabolism is crucial for ferroptosis, for which this type of cell death got its name. It is believed that the key engines of ferroptosis are reactive oxygen species (ROS), however, formed during reactions of the Fenton type and not during the operation of the mitochondrial electron transport chain . The main intracellular inhibitor of ferroptosis is glutathione peroxidase 4 (GPX4), and its activity depends on the level of glutathione (GSH), which contains cystine (therefore, when blocking X _C −Cys / Glu, antiporter synthesis of glutathione is impossible). For this reason, a lack of GSH leads to inactivation of GPX4, resulting in lipid peroxidation mediated by ROS and cell death ^{[4] [5]} . Cells in which GPX4 was knocked out die by ferroptosis ^[6] .

Recently, it has been shown that ferroptosis serves as one of the mechanisms by which the p53 tumor suppressor protein supports homeostasis in the body under stressful conditions ^{[7] [8]} . Recent studies have shown the importance of ferroptosis in maintaining homeostasis in the T-cell part of the immune system ^[9] .

Recently, it was found that under conditions of amino acid starvation, plasma factors such as the iron-transporting protein transferrin and the amino acid glutamine induce ferroptosis. As it turned out, surface cellular and the metabolic pathway for glutamine utilization, played a key role in this ^[10] .

Recent studies have shown that knockout of the cysteinyl-tRNA synthetase gene inhibits ferroptosis caused by treatment of cells with erastin ^[11] .

Chelation of iron blocks cell death induced by glutamate (which blocks the entry of cystine into the cell ^[12] ) or ROS (therefore, such cell death can be considered ferroptosis). Therefore, iron-dependent death of neurons can be stopped by metalloprotein- attenuating compounds (for example, ) and iron chelators (for example, deferoxamine). This may be important for the treatment of neurodegenerative diseases ^[4] . For example, zileuton, a lipoxygenase-5 inhibitor, blocks ferroptosis and may possibly be used in the future to combat neurodegenerative disorders ^[13] .

Ferroptosis is an important potential target for various anti-cancer drugs ^[14] . For example, sorafenib , an inhibitor of oncogenous kinases , can induce ferroptosis in hepatocellular carcinoma cells ^[15] .

As mentioned above, glutaminolysis may be involved in triggering ferroptosis. It is believed that inhibition of glutaminolysis can reduce heart damage in ischemia - ^[10] .

• Lachaier E. , Louandre C. , Ezzoukhry Z. , Godin C. , Mazière JC , Chauffert B. , Galmiche A. Ferroptosis, a new form of cell death relevant to the medical treatment of cancer (Fr.) // Medecine sciences: M / S. - 2014 .-- Vol. 30, n ^o 8-9 . - P. 779-783. - DOI : 10.1051 / medsci / 20143008016 . - PMID 25174755 .