Fig. 1.

Regulatory metabolic pathways of ferroptosis. ① Iron metabolism pathway: Fe³⁺ is imported through transferrin receptor 1 (TFR1). Fe³⁺ is converted into Fe²⁺ and released into the cytoplasm. Fe²⁺ participates in the Fenton Reaction, producing lipid ROS and causing ferroptosis. ② Ferritinophagy: Ferritin stores iron and reduces Fe²⁺ to Fe³⁺, limiting the Fenton Reaction. NCOA4 binds ferritin mediating its autophagic degradation in a process called ferritinophagy. This mechanism promotes ferroptosis. ③ GPX4 pathway: Amino acid antiporter Systemxc-(composed by SLC3A2 and SLC7A11 subunits) mediates the exchange of extracellular cystine and intracellular glutamate. It absorbs extracellular cysteine to promote glutathione synthesis. Cystine inhibition triggers ferroptosis through GSH depletion. GPX4 can catalyze the reduction of lipid peroxides thus preventing ferroptosis. ④ Lipid metabolism pathway: PUFAs and phosphatidylethanolamine (PE) derived from lipid bilayers are metabolized by ACSL4 and LPCAT3 and then oxidized by LOXs to produce lipid peroxidation. ⑤ FSP1-CoQ10-NADPH pathway: FSP1 can reduce CoQ10 to CoQH2 which, in turn, blocks lipid peroxidation. ⑥ GCH1/BH4/DHFR pathway: GCH1-BH4 pathway, which acts independently of the GPX4 pathway to regulate ferroptosis by inhibiting lipid peroxidation. ⑦ Mitochondria pathway: Iron from LIP can be transported to the mitochondria via mitochondrial ferritin (mitoferrin) and stored in ferritin. Abnormal mitochondrial iron regulation causes a massive production of ROS, which disrupts lipid peroxidation and promotes cell ferroptosis. Mitochondrial GPX4 (GPX4mito) and DHODH constitute the two main defenses against mitochondrial lipid peroxidation. In mitochondria, GPX4 attenuates ferroptosis by reducing lipid peroxidation to lipid alcohols using GSH as its cofactor. In addition, DHODH, present on the outer surface of the inner mitochondrial membrane, reduces CoQ to CoQH2, which in turn reduces lipid peroxidation and thus inhibits ferroptosis. ⑧ NRF2 pathway: NRF2 can regulate GSH homeostasis upstream, which can reduce the reduction of lipid peroxides and prevent the cells from ferroptosis. ⑨ p53 pathway: p53 can be transcribed to inhibit SLC7A11 expression and promote ferroptosis. Abbreviation used: ROS, reactive oxygen species; NCOA4, nuclear receptor coactivator 4; GPX4, glutathione peroxidase 4; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; GSH, glutathione; ACSL4, long-chain acyl-CoA synthetase-4; LPCAT3, lysophosphatidylcholine acyltransferase 3; LOXs, lipoxygenase; FSP1, ferroptosis suppressor protein 1; CoQ10, coenzyme Q10; NADPH, nicotinamide adenine dinucleotide phosphate; CoQH2, ubiquinol; GCH1, guanosine 5^′-triphosphate cyclohydrolase 1; BH4, tetrahydrobiopterin; DHFR, dihydrofolate reductase; LIP, labile iron pool; GPX4mito, mitochondrial GPX4; DHODH, dihydroorotate dehydrogenase; CoQ, coenzyme Q; NRF2, nuclear factor erythroid 2-related factor 2; PUFAs, polyunsaturated fatty acids; GTP, guanosine triphosphate; p53, tumor protein p53; ALOX12, arachidonate 12-lipoxygenase.