Research progress on ferroptosis in gliomas (Review)

Abstract

Glioma is the most prevalent type of brain tumor characterized by a poor 5-year survival rate and a high mortality rate. Malignant gliomas are commonly treated by surgery, chemotherapy and radiotherapy. However, due to toxicity and resistance to chemoradiotherapy, these treatments can be ineffective. Anxiety and depression are highly prevalent in patients with glioma, adversely affecting disease prognosis and posing societal concerns. Ferroptosis is a type of non-apoptotic, iron-dependent cell death characterized by the accumulation of lethal reactive oxygen species produced by iron metabolism, and it serves a key role in numerous diseases. Regulation of iron phagocytosis may serve as a therapeutic strategy for the development of novel glioma treatments. The present review discusses the mechanisms underlying the occurrence and regulation of ferroptosis, its role in the genesis and evolution of gliomas, and its association with glioma-related anxiety and depression. By exploring potential targets for glioma treatment, the present review provides a theoretical basis for the development of novel therapeutic strategies against glioma.

Keywords: anxiety; depression; ferroptosis; glioma; metabolism; pathway.

Figure 1.

Iron metabolism. (A) Iron absorption. DCYTB mediates the conversion of dietary non-heme iron (Fe³⁺) to ferrous ion (Fe²⁺), which is then absorbed by DMT1 in the membrane of intestinal epithelial cells. Following this intake, iron is either retained in ferritin or transferred to the basement membrane by the iron-chaperone PCBP2, where it is subsequently converted to Fe³⁺ by hephaestin. Finally, iron is discharged to the portal circulation through FPN. Tf attaches to the exported iron, which is then transported to numerous peripheral tissues. HRG-1 may uptake heme through endocytosis. Heme is degraded by heme oxygenase once it has been absorbed. Similar to the transport of non-heme iron, iron liberated from heme is transferred to portal vein blood through FPN. (B) Iron distribution. Hepcidin regulates the production of FPN by directly binding to FPN and promoting its breakdown, thus facilitating the transport of iron to the portal vein. Iron is mainly distributed in red blood cells, which transport oxygen in the blood, and tissues, such as muscle, liver and bone marrow. DCYTB, duodenal cytochrome b; DMT1, divalent metal transporter 1; PCBP2, poly(C)-binding protein 2; FPN, ferroportin; HRG-1, heme responsive gene-1; Tf, transferrin.

Figure 2.

Lipid peroxidation process. ACSL4 and LPCAT3 mediate PUFA binding to phospholipids to produce PUFA-PLs, while ALOXs further induce the production of lipid peroxides, ultimately destroying the lipid bilayer. MUFA is converted into acyl-CoA under the action of ACSL3, thereby inhibiting ferroptosis. LOX interacts with PEBP1 to produce 15-HPETE-PE, leading to ferroptotic death. CAFs produce extracellular vesicles containing miR-522, which can inhibit ROS accumulation and target ALOX15 to inhibit ferroptosis. ACSL, acyl-CoA synthetase long chain; LPCAT3, lysophosphatidylcholine acyltransferase 3; PUFA, polyunsaturated fatty acid; PUFA-PL, PUFA phospholipid; MUFA, monounsaturated fatty acid; LOX, lipoxygenase; ALOX, arachidonic acid LOX; PEBP1, phosphatidylethanolamine-binding protein 1; 15-HPETE-PE, 15-hydroperoxy-eicosa-tetraenoyl-phosphatidylethanolamine; CAFs, cancer-associated fibroblasts; miR, microRNA; ROS, reactive oxygen species; PLOOH, phospholipid hydroperoxide; iPLA2β, calcium-independent PLA2β; α-ESA, α-eleostearic a.

Figure 3.

Ferroptosis process. The main participating system in ferroptotic death is the amino acid transport system x_c⁻, composed of the SLC1A5 and SLC3A2 families. SLC, solute carrier family; ACSL4, acyl-CoA synthetase long chain family member 4; GPX4, glutathione peroxidase; GSH, glutathione; GSSG, glutathione disulfide; ROS, reactive oxygen species; TfR1, transferrin receptor 1; α-KG, α-ketoglutarate; Cys, cysteine; Cys2, cysteine2; Glu, glutamate; Gln, glutamine; LOH, lipid alcohol; LOOH, lipid hydroperoxidecid; TCA cycle, tricarboxylic acid cycle.

Figure 4.

Ferroptosis-related transcriptional regulation. Activation of TP53 exerts a minimal effect on GSH levels or GPX4 function, but it downregulates SLC7A11 and inhibits cysteine absorption. Activation of TP53 results in the production of GSH, CDKN1A, GLS2 and TIGAR. DPP4/CD26 interacts with TP53 in the nucleus and is maintained in a dormant state, whereas TP53 deficiency promotes DDP4 cell membrane localization. DDP4 induces ferroptosis by binding to NOX1 on the cell membrane. TP53, tumor protein p53; GSH, glutathione; GPX, glutathione peroxidase; SLC, solute carrier family; CDKN1A, cyclin-dependent kinase inhibitor 1A; GLS2, glutaminase 2; TIGAR, TP53-induced glycolytic regulatory phosphatase; DPP4, dipeptidyl peptidase 4; NOX, NADPH oxidase; NFE2L2, nuclear factor erythroid 2-related factor 2; ALOX, arachidonic acid lipoxygenase; FTH1, ferritin heavy chain.

Figure 5.

Ferroptosis-related defense systems. Label A represents the GPX4-GSH axis; label B represents the FSP1-CoQ10-NAD(P)H pathway; label C represents the DHODH-mediated ferroptosis defense; label D represents the GCH1-BH4-DHFR axis; and label E represents the ESCRT III-mediated plasma membrane repair system. GPX, glutathione peroxidase; GSH, glutathione; GSSG, oxidized glutathione; FSP1, ferroptosis suppressor protein 1; CoQ, coenzyme Q; CoQH₂, Coenzyme QH₂; DHODH, dihydroorotate dehydrogenase; GCH1, GTP cyclohydrolase 1; BH4, tetrahydrobiopterin; BH2, dihydrobiopterin; DHFR, dihydrofolate reductase; ESCRT, endosomal sorting complex required for transport; IPP, Isopentenyl pyrophosphate.

Figure 6.

Mechanisms of anxiety and depression in glioma. Changes in microenvironmental oxidative stress in glioma can regulate ferroptotic death through a potential mechanism involving the Sirt1/Nrf2/HO-1 pathway, thereby affecting anxiety and depression. GPX, glutathione peroxidase; ROS, reactive oxygen species; Sirt1, sirtuin 1; Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase 1.