Fig. 1

General mechanism of ferroptosis. Three main axes are described in this scheme. The first is an inhibitory axis centred around GPX4, which can convert lipid hydroperoxide into lipid alcohols. GPX4 needs glutathione (GSH) as a cofactor and its main component, cysteine, is delivered through the Xc-cystine-glutamate antiport system, which consists of two units SLC7A11 (Solute Carrier Family 7 Member 11) and SLC32A2 (Solute Carrier Family 32 Member 2). The second axis represents iron metabolism and the capability of iron to undergo the Fenton reaction, which is the main source of ROS reacting with lipids. Fe²⁺ reacts with hydroperoxide and generates the most potent oxygen radical, the hydroxyl radical. The third axis consists of lipoxygenases, and their substrates – PUFAs. Phosphorylated Heat shock protein 1 (HSPB1) acts as a negative regulator of ferroptosis by reducing cellular iron uptake and lipid ROS production [281]. Another factor elevating the Fe²⁺ pool is ferritinophagy, which is mediated by a selective cargo receptor Nuclear receptor coactivator 4 (NCOA4). The third axis is driven by lipoxygenases (LOXs) which allow enzymatic oxidation of PUFAs to form. PUFAs-OOH adding to the lipid ROS pool. All three mentioned axes increase the amount of lipid ROS in the membrane which then leads to its rupture and ferroptosis occurs