Relevance of Ferroptosis to Cardiotoxicity Caused by Anthracyclines: Mechanisms to Target Treatments

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  FIGURE 1. Mechanisms of ferroptosis. Ferroptosis is essentially an iron-dependent lipid peroxidation. Intracellular iron overload is a necessary condition for ferroptosis, and lipid peroxidation is the presentation form of ferroptosis. TfR1, transferrin receptor 1; FPN, ferroportin; Cys, cysteine; GSH, glutathione; GPX4, glutathione peroxidase 4; STEAP3, six-transmembrane epithelial antigen of the prostate 3; DMT1, divalent metal transporter 1; HO-1, heme oxygenase 1; NADPH, nicotinamide adenine dinucleotide phosphate; FSP1, ferroptosis suppressor protein 1; PUFA, polyunsaturated fatty acids; GCH1, GTP cyclohydrolase-1; BH4/BH2, tetrahydrobiopterin/dihydrobiopterin; LOXs, lipoxygenases; PL•, phospholipid radical; PLOO•, phospholipid peroxyl radical; PLOOH, phospholipid hydroperoxide; α-TOH, α-tocopherol.

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  FIGURE 2. The mechanisms of DIC based on ferroptosis. DOX induces ferroptosis in cardiomyocytes involves two major mechanisms: one is to disrupt iron homeostasis and the other is to promote lipid peroxidation. The targets of DOX on iron disorder are Tf, ferritin, HO-1, FXN, ABCB8, IRE, IRP, and KCNQ1OT1m6A. The targets of DOX for lipid peroxidation are ROS, SOD, GPX4, and GSH. The site of iron death in cardiomyocytes is probably the mitochondria. TfR1, transferrin receptor 1; Tf, transferrin; DOX, doxorubicin; IRP, iron regulatory protein; METTL14, methyltransferase-like 14; Nrf2, nuclear factor (erythroid-derived 2)-like 2; LIP, labile iron pool; HO-1, heme oxygenase 1; ROS, reactive oxygen species; SOD, superoxide dismutase; Cys, cysteine; GSH, glutathione; GPX4, glutathione peroxidase 4; FPN, ferroportin; FXN, frataxin; ABCB8, ABC protein-B8; O2, oxygen; O2•–, active oxygen; FtMt, mitochondrial ferritin; CL, cardiolipin; OH•, hydroxyl radical.

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  FIGURE 3. Prevention and SOD treatment of AIC based on ferroptosis. The mechanism of preventing ferroptosis of cardiomyocytes is mainly in two aspects. One is to inhibit iron accumulation, and the other is to inhibit lipid peroxidation. Iron chelators can play a role through the former. The effects of RTAs, anti-diabetic medications, and energy-stress inducers are mainly attributed to the latter. TfR1, transferrin receptor 1; FPN, ferroportin; DOX, doxorubicin; DNR, daunorubicin; LIP, labile iron pool; HO-1, heme oxygenase 1; ROS, reactive oxygen species; Fer-1, ferrostatin-1; DFO, deferoxamine; DXZ, dexrazoxane; PUFA, polyunsaturated fatty acids; ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; EMPA, empagliflozin; Sit, sitagliptin; 2DG, 2-deoxy-d-glucose; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; HMGB1, high mobility group box 1; HO-1, heme oxygenase 1; FTH, ferritin heavy chain; NF-κB, nuclear factor-kappa B; α-TOH, α-tocopherol; CoQ10, coenzyme Q10; Lip-1, liproxstatin-1; BHT, butylated hydroxytoluene; Acot1, acyl-CoA thioesterase 1; TEMPO, 2,2,6,6-tetramethylpiperidin-N-oxyl; Met, metformin.