Fig. 1
From: The multifaceted role of ferroptosis in infection and injury and its nutritional regulation in pigs
The core regulatory mechanisms and defense systems of ferroptosis. Ferroptosis is characterized by iron-dependent lipid peroxidation and overproduction of ROS. Fe3+ binds to TF and is transported to into the cell by TFR1. Ferritin (FTH1, FTL) is the main protein that regulates the storage and utilization of intracellular iron. The excess Fe2+ can be oxidized to Fe3+ and exported by FPN. Increased iron uptake, decreased iron storage, and inadequate iron efflux can lead to the increase of LIP and subsequent initiation of ferroptosis. The free PUFAs are catalyzed by ACSL4 and LPCAT3 to form PUFA-PLs. In addition, some membrane proteins (such as COXs, NOXs, and LOXs) can accelerate the process of lipid peroxidation. The GPX4-GSH antioxidant system is the main cellular defense mechanism against ferroptosis, which is initiated by System Xc− comprised of SLC3A2 and SLC7A11. Several GPX-independent defense systems have been identified, including the FSP1-CoQH2 system, the DHODH-CoQH2 system, and the GCH1-BH4 system. ACSL4, acyl-CoA synthetase long-chain family member 4; BH4, tetrahydrobiopterin; CoQ10H2, ubiquinol; CoQ10, coenzyme Q10; COXs, cyclooxygenases; DHODH, dihydroorotate dehydrogenase; FPN, Ferroportin; FSP1, ferroptosis suppressor protein 1; FTH, ferritin heavy chain; FTL, ferritin light chain; GCL, glutamate-cysteine ligase; GSS, glutathione synthetase; GSSG, oxidized glutathione; GPX4, glutathione peroxidase 4; GCH1, guanosine triphosphate cyclohydrolase 1; GSH, glutathione; LIP, labile iron pool; LOXs, lipoxygenases; LPCAT3, lysophosphatidylcholine acyltransferase 3; NOXs, NADPH oxidases; PUFA, polyunsaturated fatty acid; PUFA-PL, polyunsaturated fatty acid-containing phospholipid; ROS, reactive oxygen species; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; TF, transferrin; TFR1, transferrin receptor 1