Fig. 1: The main metabolic processes regulating ferroptosis and GPX4 activity.
From: Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion
The key ferroptosis regulator glutathione peroxidase 4 (GPX4) and upstream events modulating sensitivity are shown. Cysteine and glutathione (reduced) (GSH) availability supported by cystine uptake or the transsulfuration pathway is at the core of ferroptosis by providing reducing equivalents for the optimal function of GPX4 (refs3,4). This has been recently recognized as an important checkpoint controlled by the known tumour suppressors BRCA1-associated protein 1 (BAP1)47 and p53 (ref.22), generating an intrinsic sensitivity to ferroptosis. The mevalonate pathway is involved in ferroptosis by generating a series of biomolecules with potential anti-ferroptotic activity such as squalene41, ubiquinone40 and isopentenyl-pyrophosphate (PP)21, the last of which stabilizes the selenocysteine-specific tRNA required for efficient GPX4 translation. Iron uptake via the transferrin receptor or degradation of ferritin16,17 iron stores increases the labile iron pool, thereby sensitizing cells to ferroptosis via facilitation of a Fenton-like reaction of pre-formed lipid hydroperoxides. Iron uptake and processing, acyl-CoA synthetase long chain family member 4 (ACSL4)-dependent shaping of the cellular phospholipidome7 and the tricarboxylic acid (TCA) cycle are additional cellular processes that may contribute to ferroptosis sensitization. Recently, the impact of the hypoxia-inducible factor (HIF) system on fatty acid (FA) metabolism has been appreciated20, and the mobilization of lipid from droplets leads to modulation of ferroptosis sensitivity, depending on the FA composition of the latter. Additionally, channelling of polyunsaturated fatty acids (PUFAs) for catabolic purposes lowers their incorporation into phospholipids, thus decreasing sensitivity to ferroptosis6,20. α-KG, α-ketoglutarate; AA, arachidonic acid; ABCA1, ATP-binding cassette subfamily A member 1; ATGL, adipose triglyceride lipase (also known as PNPLA2); CoQ10, coenzyme Q10; CPT, carnitine palmitoyltransferase; DGAT, diacylglycerol O-acyltransferase; DPP4, dipeptidyl peptidase 4; ER, endoplasmic reticulum; 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.
