Fig. 1: Molecular mechanisms of ferroptosis.

Ferroptosis is typically triggered by iron-dependent lipid peroxidation. The cystine/glutamate transporter (also known as system xc-) imports cystine into cells with a 1:1 counter-transport of glutamate. Once inside the cells, cystine can be oxidated into cysteine, which is used to synthesize GSH. Taken as a reducing cofactor, GSH is in the reaction of reducing lipid hydroperoxides to lipid alcohols under the capability of glutathione peroxidase GPX4. Transsulfuration pathway is involved in supporting the availability of cystine and reduced GSH. Respectively, the mevalonate pathway generates a series of biomolecules and then drives ferroptosis. Several proteins (including serotransferrin, lactotransferrin, Transferrin receptor (TFRC), ferroportin 1 (FPN1), nuclear receptor co-activator 4 (NCOA4)) control ferroptosis through the regulation of iron metabolism. Fe³⁺ could be internalized into cells through three distinct pathways including lactotransferrin, haemin and serotransferrin-TFRC-SLC11A2 pathway, during which Fe³⁺ is reduced and storage in the liable iron pool. Cells have evolved at least four systems inhibiting ferroptosis with different subcellular localizations to decrease lipid peroxides. The GPX4-GSH system can collaborate with FSP1-CoQH2 system on the plasma membrane and can also cooperate with DHODH-CoQH2 system on mitochondrial membrane. Of late, the impact of the hypoxia-inducible factor (HIF) system on fatty acid (FA) metabolism has been depicted. α-KG α-ketoglutarate, AA arachidonic acid, ABCA1 ATP- binding cassette subfamily A member 1, ACSL4 Long- chain fatty acid–CoA ligase 4, ATGL adipose triglyceride lipase (also known as PNPL A2), ALOXs Arachidonate lipoxygenases, CoQ coenzyme Q10, CPT carnitine palmitoyl transferase, DGAT diacylglycerol O- acyltransferase, DPP4 dipeptidyl peptidase 4, ETC electron transport chain, ER endoplasmic reticulum, FLVCR2, FPN1 ferroportin 1 (also known as SLC40A1), GLS glutaminase, GSR glutathione disulfide reductase, GSSG glutathione disulfide, HILPDA hypoxia-inducible lipid droplet- associated, HMGCR HMG-CoA reductase, LOX lipoxygenase, LPCAT lyso-phosphatidylcholine acyltransferase, NCOA4 nuclear receptor co-activator 4, NOX1 NADPH oxidase 1, OGDH oxoglutarate dehydrogenase, OXPHOS oxidative phosphorylation, PE phosphatidylethanolamine, PLIN2 perilipin 2, PS phosphatidylserine, SREBP2 sterol regulatory element binding protein 2, system xc- cystine–glutamate antiporter, TFRC transferrin receptor, GCH1 GTP cyclohydrolase 1, HMOX1 Heme oxygenase, SLC48A1 solute carrier family 48 member 1, SLC46A1 solute carrier family 46 member 1, SLC7A11 solute carrier family 7 member 11, SLC3A2 solute carrier family 3 member 2, SLC11A2 solute carrier family 11 member 2.