Fig. 3: Ferroptosis and fatty acid metabolism.

Fatty acid metabolism contains anabolism and catabolism. Fatty acid anabolism includes synthesis, elongation and desaturation. Citrate can be utilized to synthesize malony-CoA by ACLY and ACC1. ACC1 is phosphorylated and suppressed by AMPK, which inhibits the activity of FASN. FASN catalyzes the reaction of malony-CoA to palmitate, which can promote the deubiquitination of HIF-1α, thus increasing the expression of SLC7A11 and blocking ferroptosis. SREBP1 can regulate the activity of SCD1, SCD5 and BCAT2, which regulate ferroptosis through increasing the levels of MUFA and the activity of GPX4, respectively. ACSLs catalyze the decomposition of long-chain fatty acids. ACSL4, is regulated by RB1, PKCβII and CDK1, which catalyzes the formation of PUFA-CoA. PUFA-CoA can be converted to PUFA-PE or PUFA-CE by LPCAT3 and SOAT1, respectively. PUFA-PLs are used to produced lipid peroxides by LOXs, thus sensitize cancer cells to ferroptosis. ACSL3 is another member of ACSL family, which catalyzes the transformation of OA to MUFA, thus acting as a suppressor of ferroptosis. ACLY ATP citrate lyase; ACC1, acetyl-CoA-carboxylase 1, FASN fatty acid synthase, HIF-1α hypoxia-inducible factor-1α, SLC7A11 solute carrier family 7 member 11, SLC3A2 solute carrier family 3 member 2, CB1 cannabinoid receptor 1, ERK extracellular signal-regulated kinase, TSC2 tuberous sclerosis complex 2, AKT protein kinase B, PI3K phosphoinositide 3-kinase, mTORC1 mammalian target of rapamycin complex 1, AMPK adenosine 5′-monophosphate (AMP)-activated protein kinase, ASS1 argininosuccinate synthetase 1, SPAG4 sperm associated antigen 4, SREBP1 sterol responsive element binding protein 1, SCD1 stearoyl-CoA desaturase-1, SCD5 stearoyl-CoA desaturase-5, SFA saturated fatty acids, MUFA monounsaturated fatty acids, BCAT2 Branched-chain amino acid aminotransferase 2, BCAA branched-chain amino acids. BCKA branched-chain α-ketoacids, αKG alpha-ketoglutaric acid, Glu glutamate, FADS2 fatty acid desaturase 2, ZEB1 zinc finger E-box-binding homeobox protein 1, GSH reduced glutathione, GPX4 glutathione peroxidase 4, PKCβII protein kinase C βII, RB1 retinoblastomal 1, PUFA polyunsaturated fatty acids, ACSL4 long-chain acyl-CoA synthetase 4, LPCAT3 lysophosphatidylcholine acyltransferase 3, SOAT1 sterol O-acyltransferase 1, PE phosphatidylethanolamine, CE cholesterol ester, LOXs lipoxygenases, CDK1 cyclin-dependent kinase 1, UBR5 ubiquitin ligase E3 component N-recognition protein 5, Met methionine, SAM S-adenosylmethionine, ACSL3 long-chain acyl-CoA synthetase 3, OA oleic acid (Created with BioRender.com).