Key markers of ferroptosis

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Introduction. Ferroptosis is a type of programmed cell death associated with excessive accumulation of endogenous iron in the cell, accompanied by the production of reactive oxygen species and, as a result, lipid peroxidation. The literature review examines the key markers of ferroptosis, which is one of the types of programmed cell death other than apoptosis, necroptosis, pyroptosis, etc.

Purpose: to collect and process information on the main markers of ferroptosis, which will allow to adapt and optimize the processes of its study.

Material and methods: analysis of literary sources of domestic and foreign origin on a given topic.

Results: articles have been found and analyzed, including those from the last 5 years, confirming the prospects of ferroptosis as a potential pharmacological target. Conclusion. Understanding the main signs of the launch of this process is an integral part of the research work aimed at finding new therapeutic targets associated with the launch of ferroptosis, which, in turn, represents a promising pharmacological model, since It has a high potential for the future treatment of drug-resistant types of pathologies.

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作者简介

Maria Tokhtueva

Federal State Autonomous Educational Institution of Higher Education “Ural Federal University named after the first President of Russia B.N. Yeltsin” of the Ministry of Science and Higher Education of the Russian Federation

编辑信件的主要联系方式.
Email: maria.tokhtueva@urfu.ru
ORCID iD: 0000-0002-2895-336X

research engineer at the Laboratory of Primary Bioscreening, Cellular and Gene Technologies of the Scientific, Educational and Information Center for Chemical and Pharmaceutical Technologies of the Institute of Chemical Technology

俄罗斯联邦, Mira str., 19, Yekaterinburg, 620002

Vsevolod Melekhin

Federal State Autonomous Educational Institution of Higher Education “Ural Federal University named after the first President of Russia B.N. Yeltsin” of the Ministry of Science and Higher Education of the Russian Federation; Federal State Budgetary Educational Institution of Higher Education “Ural Federal State Medical University”, Healthcare Ministry of Russia

Email: v.v.melekhin@urfu.ru
ORCID iD: 0000-0003-3107-8532

PhD of Medical Sciences, Associate Professor, Head of the Laboratory of Primary Bioscreening, Cellular and Gene Technologies of the Scientific, Educational and Information Center for Chemical and Pharmaceutical Technologies of the Institute of Chemical Technology of the FSAEI HE “Ural Federal University named after the first President of Russia B.N. Yeltsin”; Associate Professor of the Department of Medical Biology and Genetics of the FSAEI HE “Ural Federal State Medical University”

俄罗斯联邦, Mira str., 19, Yekaterinburg, 620002; Repina str., 3, Yekaterinburg, 620028

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2. Fig. 1. The mechanism of ferroptosis: Fe3+ is imported into the cell through the Tf/TFR1 system (Tf – transferrin, TFR1 – transferrin receptor 1), after which it is localized in the endosome and converted to Fe2+ using STEAP3 ferrieductase. Then the ferrous ion membrane transport protein (DMT1 or SLC11A2) mediates the release of Fe2+, the excess of which increases the intensity of the Fenton reaction, generating reactive oxygen species (ROS), causing lipid peroxidation (POL). The POL chain reaction can also be triggered by iron-dependent enzymes lipoxygenases (LOX) or oxidoreductases (POR). Normally, iron is disposed of from the cell by ferroportin (SLC11A3) or into the mitochondrial metabolic system, and is also concentrated in ferritin, consisting of a light (FTL) and heavy chain (FTH1), but if this system is disrupted, ferroptosis is triggered

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3. Fig. 2. The chain reaction of the formation of fatty acid peroxide radicals is an increased production of particles having an unpaired electron (the structure of lipids includes a CH2-group from which a free radical (initiator of oxidation) can take away an electron, thereby converting a lipid containing this acid into a free radical CH•, triggering a chain reaction). (a) LH – lipid, which is part of the structure of cell membranes, reacts with ROS (OH•), forming the free radical L•, which, in turn, attaches O2, resulting in the formation of the peroxyradical LOO•, which subsequently acts as an inducer of the oxidative process and takes away an electron from LH to form L• and LOOH lipid peroxide; (b) the formation of LOOH lipid peroxide can also be initiated enzymatically by lipoxygenases (LOX), as a result of which the excess LOOH in the reaction catalyzed by iron turns into the alkyl radical LO•, inducing the oxidation of LH, with the formation of L• and, as a result, the launch of a new oxidation reaction

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4. Fig. 3. The system of formation of lipid hydroperoxides in cells: polyunsaturated fatty acid (PUFA) under the action of a synthetase of a long-chain member of the family 4 (ACSL4) is converted into a PUFA-CoA ester, after which, in a reaction catalyzed by lysophosphatidylcholine acyltransferase 3 (LPCAT3), into glycerophospholipids (PL-PUFA), which under the action of lipoxygenases (LOX) or oxidoreductases (POR) form polyunsaturated fatty acid peroxides (PL-PUFA-OOH). A long-chain member of the acyl-CoA synthetase 3 (ACSL3) family, in turn, converts monounsaturated fatty acids (MUFA) into acyl-CoA ester to bind to membrane phospholipids, thereby protecting cells from ferroptosis

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5. Fig. 4. Antioxidant protection systems of the cell, in violation of which there is no proper utilization of reactive oxygen species and oxidative processes are initiated in the form of lipid peroxidation and, as a result, ferroptosis: 1 – Xc– system (amino acid antiporter), mediating the transport of cysteine into the cell, which is a precursor of GSH (glutamate-cysteine ligase), which is the main reducing agent a substrate for GPX4 (selenium–containing antioxidant enzyme, glutathione peroxidase 4) – a regulator of the level of hydroperoxides in complex lipids (due to their inactivation reaction); 2 – the GTP (guanosine-5’-triphosphate), GCH1 (cyclohydrolase-1) and BH4 (tetrahydrobiopterin) pathway, which creates a redox cycle leading to a decrease in the number of oxidative radicals due to their conversion into inactive forms by BH4; 3 – the FSP1 system (ferroptosis suppressor protein 1), which regulates the reduction of CoQ10 (extramitochondrial ubiquinone) to CoQH2 (ubiquinol), which is a blocker of the formation of hydroperoxides in cells

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