# Ferroptosis in Glioblastoma and Neuroblastoma: Molecular Mechanisms and Novel Therapeutic Strategies **Authors:** Zhaoyang Liu, Zihan Ma, Kexin Yang, Hongwei Fan PMC · DOI: 10.3390/cimb48030267 · 2026-03-03 ## TL;DR This paper reviews how ferroptosis, a type of cell death, influences brain and nerve tumors and explores new treatment strategies. ## Contribution The paper provides a systematic synthesis of ferroptosis mechanisms and therapeutic strategies in glioblastoma and neuroblastoma. ## Key findings - Ferroptosis is regulated by lipid peroxidation, iron, and glutathione metabolism in CNS tumors. - Ferroptosis regulation varies between glioblastoma and neuroblastoma due to distinct developmental and metabolic contexts. - Targeting ferroptosis offers new diagnostic and therapeutic opportunities for nervous system malignancies. ## Abstract Malignant neoplasms arising from the central nervous system (CNS), particularly glioblastoma (GBM) as well as neuroblastoma (NB), represent a formidable global health burden owing to their aggressive biological behavior and dismal clinical outcomes. Ferroptosis—an iron-dependent form of regulated cell death distinct from apoptosis, autophagy, and necrosis—has emerged as a critical regulatory nexus in the progression and therapeutic response of these malignancies. Characterized by iron-catalyzed lipid peroxidation, ferroptosis is tightly governed by the metabolic interplay among lipids, iron, and glutathione, profoundly influencing tumorigenesis, tumor progression, and therapeutic resistance. In this review, we systematically synthesize current knowledge on ferroptosis in GBM and NB, specifically contrasting how developmental origins and metabolic contexts shape their regulatory mechanisms. We further integrate recent advances in the diagnostic and therapeutic landscape of nervous system tumors, with a particular emphasis on ferroptosis-targeted strategies. Overall, this work aims to provide a conceptual framework linking ferroptosis regulation to tumor context, thereby offering mechanistic insights and future directions for the precision management of nervous system malignancies. ## Linked entities - **Diseases:** glioblastoma (MONDO:0018177), neuroblastoma (MONDO:0005072) ## Full-text entities - **Genes:** FTO (FTO alpha-ketoglutarate dependent dioxygenase) [NCBI Gene 79068] {aka ALKBH9, BMIQ14, GDFD, IFEX9}, HMOX1 (heme oxygenase 1) [NCBI Gene 3162] {aka HMOX1D, HO-1, HSP32, bK286B10}, Slc7a11 (solute carrier family 7 (cationic amino acid transporter, y+ system), member 11) [NCBI Gene 26570] {aka 9930009M05Rik, sut, xCT}, AKR1C1 (aldo-keto reductase family 1 member C1) [NCBI Gene 1645] {aka 2-ALPHA-HSD, 20-ALPHA-HSD, DD1, DD1/DD2, DDH, DDH1}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, FMOD (fibromodulin) [NCBI Gene 2331] {aka FM, SLRR2E}, LINC01088 (long intergenic non-protein coding RNA 1088) [NCBI Gene 100505875], HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1) [NCBI Gene 3181] {aka HNRNPA2, HNRNPB1, HNRPA2, HNRPA2B1, HNRPB1, IBMPFD2}, PRDX6 (peroxiredoxin 6) [NCBI Gene 9588] {aka 1-Cys, AOP2, HEL-S-128m, LPCAT-5, NSGPx, PRX}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, TF (transferrin) [NCBI Gene 7018] {aka HEL-S-71p, PRO1557, PRO2086, TFQTL1}, USP7 (ubiquitin specific peptidase 7) [NCBI Gene 7874] {aka C16DELp13.2, DEL16P13.2, HAFOUS, HAUSP, TEF1}, OSBPL9 (oxysterol binding protein like 9) [NCBI Gene 114883] {aka ORP-9, ORP9}, PRMT1 (protein arginine methyltransferase 1) [NCBI Gene 3276] {aka ANM1, HCP1, HRMT1L2, IR1B4}, PLB1 (phospholipase B1) [NCBI Gene 151056] {aka PLB, PLB/LIP}, G0S2 (G0/G1 switch 2) [NCBI Gene 50486], TEP1 (telomerase associated protein 1) [NCBI Gene 7011] {aka TLP1, TP1, TROVE1, VAULT2, p240}, Psmc3 (proteasome (prosome, macropain) 26S subunit, ATPase 3) [NCBI Gene 19182] {aka TBP-1}, SLC7A11 (solute carrier family 7 member 11) [NCBI Gene 23657] {aka CCBR1, xCT}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, IFNA10 (interferon alpha 10) [NCBI Gene 3446] {aka IFN-alphaC}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, NCOA4 (nuclear receptor coactivator 4) [NCBI Gene 8031] {aka ARA70, ELE1, PTC3, RFG}, IGHG2 (immunoglobulin heavy constant gamma 2 (G2m marker)) [NCBI Gene 3501], BMI1 (BMI1 proto-oncogene, polycomb ring finger) [NCBI Gene 648] {aka FLVI2/BMI1, PCGF4, RNF51, flvi-2/bmi-1}, GPX4 (glutathione peroxidase 4) [NCBI Gene 2879] {aka GPx-4, GSHPx-4, MCSP, PHGPx, SMDS, snGPx}, GCLC (glutamate-cysteine ligase catalytic subunit) [NCBI Gene 2729] {aka CNSHA7, GCL, GCS, GLCL, GLCLC}, EIF2A (eukaryotic translation initiation factor 2A) [NCBI Gene 83939] {aka CDA02, EIF-2A, MST089, MSTP004, MSTP089}, DHODH (dihydroorotate dehydrogenase (quinone)) [NCBI Gene 1723] {aka DHOdehase, POADS, URA1}, TCF4 (transcription factor 4) [NCBI Gene 6925] {aka CDG2T, E2-2, FCD2, FECD3, ITF-2, ITF2}, ATF4 (activating transcription factor 4) [NCBI Gene 468] {aka CREB-2, CREB2, TAXREB67, TXREB}, CBS (cystathionine beta-synthase) [NCBI Gene 875] {aka HIP4}, ERCC1 (ERCC excision repair 1, endonuclease non-catalytic subunit) [NCBI Gene 2067] {aka COFS4, RAD10, UV20}, IFI16 (interferon gamma inducible protein 16) [NCBI Gene 3428] {aka IFNGIP1, PYHIN2}, TRIM59 (tripartite motif containing 59) [NCBI Gene 286827] {aka IFT80L, MRF1, RNF104, TRIM57, TSBF1}, PROM2 (prominin 2) [NCBI Gene 150696] {aka PROML2}, ALKBH5 (alkB homolog 5, RNA demethylase) [NCBI Gene 54890] {aka ABH5, OFOXD, OFOXD1}, MYCN (MYCN proto-oncogene, bHLH transcription factor) [NCBI Gene 4613] {aka FGLDS1, MODED, MPAPA, MYCNsORF, MYCNsPEP, N-myc}, EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) [NCBI Gene 1965] {aka EIF-2, EIF-2A, EIF-2alpha, EIF2, EIF2A}, ACSL3 (acyl-CoA synthetase long chain family member 3) [NCBI Gene 2181] {aka ACS3, FACL3, LACS 3, LACS3, PRO2194}, CDC27 (cell division cycle 27) [NCBI Gene 996] {aka ANAPC3, APC3, CDC27Hs, D0S1430E, D17S978E, H-NUC}, METTL3 (methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit) [NCBI Gene 56339] {aka IME4, M6A, MT-A70, Spo8, hMETTL3}, KEAP1 (kelch like ECH associated protein 1) [NCBI Gene 9817] {aka INrf2, KLHL19}, SMG1 (SMG1 nonsense mediated mRNA decay associated PI3K related kinase) [NCBI Gene 23049] {aka 61E3.4, ATX, LIP}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, SLC25A5 (solute carrier family 25 member 5) [NCBI Gene 292] {aka 2F1, AAC2, ANT2, T2, T3}, SLC40A1 (solute carrier family 40 member 1) [NCBI Gene 30061] {aka FPN, FPN1, HFE4, IREG1, MST079, MSTP079}, GSS (glutathione synthetase) [NCBI Gene 2937] {aka CNSHA6, GSHS, HEL-S-64p, HEL-S-88n}, PRKCA (protein kinase C alpha) [NCBI Gene 5578] {aka AAG6, PKC-alpha, PKCA, PKCI+/-, PKCalpha}, Ptgs2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 19225] {aka COX2, Cox-2, PES-2, PGHS-2, PHS II, PHS-2}, HSPB1 (heat shock protein family B (small) member 1) [NCBI Gene 3315] {aka CMT2F, HEL-S-102, HMN2B, HMND3, HS.76067, HSP27}, APOC1 (apolipoprotein C1) [NCBI Gene 341] {aka APOC1B, Apo-CI, ApoC-I, apo-CIB, apoC-IB}, AURKA (aurora kinase A) [NCBI Gene 6790] {aka AIK, ARK1, AURA, BTAK, PPP1R47, STK15}, ALOX15 (arachidonate 15-lipoxygenase) [NCBI Gene 246] {aka 12-LOX, 15-LOX, 15-LOX-1, LOG15}, FTH1 (ferritin heavy chain 1) [NCBI Gene 2495] {aka FHC, FTH, FTHL6, HFE5, NBIA9, PIG15}, PTX3 (pentraxin 3) [NCBI Gene 5806] {aka TNFAIP5, TSG-14}, ODC1 (ornithine decarboxylase 1) [NCBI Gene 4953] {aka BABS, NEDBA, NEDBIA, ODC}, STEAP3 (STEAP3 metalloreductase) [NCBI Gene 55240] {aka AHMIO2, STMP3, TSAP6, dudlin-2, dudulin-2, pHyde}, FBXL2 (F-box and leucine rich repeat protein 2) [NCBI Gene 25827] {aka FBL2, FBL3}, ECH1 (enoyl-CoA hydratase 1) [NCBI Gene 1891] {aka HPXEL} - **Diseases:** hepatocellular carcinoma (MESH:D006528), FSP1 deficiency (OMIM:601308), non-small cell lung cancer (MESH:D002289), toxicity (MESH:D064420), central nervous system disorders (MESH:D002493), Malignant neoplasms of the central nervous system (MESH:D016543), mitochondrial dysfunction (MESH:D028361), injury to (MESH:D014947), pancreatic ductal adenocarcinoma (MESH:D021441), triple-negative breast cancer (MESH:D064726), tumorigenesis (MESH:D063646), metastasis (MESH:D009362), Nervous System Tumors (MESH:D009423), necrosis (MESH:D009336), brain and other nervous system cancers (MESH:D001932), hypoxic (MESH:D002534), solid (MESH:D018250), nervous system malignancies (MESH:D010524), NB (MESH:D009447), Glioma (MESH:D005910), cancers (MESH:D009369), GBM (MESH:D005909), Hypoxia (MESH:D000860) - **Chemicals:** mevalonate (MESH:D008798), N6-methyladenosine (MESH:C010223), m6A (MESH:C005955), DHA (MESH:C027493), Plumbagin (MESH:C014758), BHT (MESH:D002084), Iron (MESH:D007501), SAHA (MESH:D000077337), NADPH (MESH:D009249), WA (MESH:C009684), Procyanidin B1 (MESH:C479579), peroxyl radical (MESH:C049375), Lipid (MESH:D008055), alpha-Tocopherol (MESH:D024502), CoQ10 (MESH:C024989), quinone (MESH:C004532), Fe2+ (-), cholesterol (MESH:D002784), pyrimidine (MESH:C030986), curcumin (MESH:D003474), Ala (MESH:D000409), thiol (MESH:D013438), glutamine (MESH:D005973), pomiferin (MESH:C474837), MDA (MESH:D008315), Regorafenib (MESH:C559147), paclitaxel (MESH:D017239), ATP (MESH:D000255), CQ (MESH:D002738), disulfiram (MESH:D004221), PE (MESH:C483858), heme (MESH:D006418), sorafenib (MESH:D000077157), nucleotide (MESH:D009711), VLX600 (MESH:C000602558), Fatostatin (MESH:C545733), Adrenic acid (MESH:C011395), PUFA (MESH:D005231), docosahexaenoic acid (MESH:D004281), NADH (MESH:D009243), ROS (MESH:D017382), Cystine (MESH:D003553), LOOH (MESH:D008054), GSSG (MESH:D019803), 15,16-Dihydrotanshinone I (MESH:C000713095), GSH (MESH:D005978), sulfasalazine (MESH:D012460), phospholipid (MESH:D010743), PTC596 (MESH:C000712133), Cys (MESH:D003545), arachidonic acid (MESH:D016718), 7-DHC (MESH:C016705), Asn (MESH:D001216), TMZ (MESH:D000077204), brucine (MESH:C083806), AA (MESH:D000596), H2O2 (MESH:D006861), erastin (MESH:C477224), Glu (MESH:D018698), CoQ (MESH:D014451) - **Species:** Maclura pomifera (Osage orange, species) [taxon 3496], Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090] - **Mutations:** glutamate-cysteine, R132H, asparagine/alanine ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13025200/full.md --- Source: https://tomesphere.com/paper/PMC13025200