Beyond frroptosis induction: Defining ferroptosis vulnerability in glioblastoma

Jenna K Minami

1,*,#

Jennifer J Salinas

1,#

Caitlyn E Loo

Weaverly Colleen Lee

Scott J Dixon

2,†

David A Nathanson

1,†

Affiliation +

*Correspondence to: Jenna K Minami, University of California, Los Angeles, CA 90095, USA. E-mail: JMinami@mednet.ucla.edu.

Ferroptosis Oxid Stress. 2027;3:202637. 10.70401/fos.2026.0048

Received: July 14, 2026Accepted: September 30, 2026Published: October 08, 2026

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Glioblastoma (GBM) is the most lethal primary brain tumor, with minimal therapeutic progress over the past two decades. A defining feature of GBM is its intrinsic resistance to apoptosis, prompting interest in activating alternative cell death pathways such as ferroptosis, an iron-dependent process driven by lipid peroxidation. In GBM, ferroptosis represents a context-dependent vulnerability that arises directly from tumor specific lipid metabolic reprogramming. Here, we outline a unifying framework in which ferroptosis sensitivity is governed by three interdependent axes: availability of oxidizable lipids, redox buffering, and iron handling. Genetic alterations common in GBM, such as CDKN2A loss, EGFR amplification or mutation, and PTEN loss, reshape these axes to either suppress or promote ferroptotic cell death. This susceptibility is further modulated by cellular state and the tumor microenvironment. Effective therapeutic targeting will require biomarker-driven patient stratification, rational combination strategies, and the development of brain-penetrant agents with tumor-selective activity. Together, this framework positions ferroptosis not as a universally inducible death pathway in GBM, but as a context-dependent vulnerability that can be therapeutically exploited in tumors already poised near the ferroptosis threshold.

Keywords

Glioblastoma, lipid Metabolism, ferroptosis, cell death

References

1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.

[DOI] [PubMed]
2. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488(7412):522-526.

[DOI] [PubMed] [PMC]
3. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756-760.

[DOI] [PubMed]
4. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro-Oncology. 2021;23(8):1231-1251.

[DOI] [PubMed] [PMC]
5. Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, et al. Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacol Res. 2021;171:105780.

[DOI] [PubMed] [PMC]
6. Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462-477.

[DOI] [PubMed] [PMC]
7. Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98-110.

[DOI] [PubMed] [PMC]
8. Wyllie AH, Kerr JFR, Currie AR. Cell death: The significance of apoptosis. Int Rev Cytol. 1980;68:251-306.

[DOI] [PubMed]
9. Hannun YA. Apoptosis and the dilemma of cancer chemotherapy. Blood. 1997;89(6):1845-1853.

[DOI] [PubMed]
10. Fernandez EG, Mai WX, Song K, Bayley NA, Kim J, Zhu H, et al. Integrated molecular and functional characterization of the intrinsic apoptotic machinery identifies therapeutic vulnerabilities in glioma. Nat Commun. 2024;15:10089.

[DOI] [PubMed] [PMC]
11. Ziegler DS, Kung AL, Kieran MW. Anti-apoptosis mechanisms in malignant gliomas. JCO. 2008;26(3):493-500.

[DOI] [PubMed]
12. Minami JK, Morrow D, Bayley NA, Fernandez EG, Salinas JJ, Tse C, et al. CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis. Cancer Cell. 2023;41(6):1048-1060.e9.

[DOI] [PubMed] [PMC]
13. Neftel C, Laffy J, Filbin MG, Hara T, Shore ME, Rahme GJ, et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell. 2019;178(4):835-849.e21.

[DOI] [PubMed] [PMC]
14. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396-1401.

[DOI] [PubMed] [PMC]
15. Greenwald AC, Darnell NG, Hoefflin R, Simkin D, Mount CW, Gonzalez Castro LN, et al. Integrative spatial analysis reveals a multi-layered organization of glioblastoma. Cell. 2024;187(10):2485-2501.e26.

[DOI] [PubMed] [PMC]
16. Lee WC, Dixon SJ. Mechanisms of ferroptosis sensitization and resistance. Dev Cell. 2025;60(7):982-993.

[DOI] [PubMed] [PMC]
17. Pope LE, Dixon SJ. Regulation of ferroptosis by lipid metabolism. Trends Cell Biol. 2023;33(12):1077-1087.

[DOI] [PubMed] [PMC]
18. Magtanong L, Mueller GD, Williams KJ, Billmann M, Chan K, Armenta DA, et al. Context-dependent regulation of ferroptosis sensitivity. Cell Chem Biol. 2022;29(9):1409-1418.e6.

[DOI] [PubMed] [PMC]
19. Liang D, Minikes AM, Jiang X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell. 2022;82(12):2215-2227.

[DOI] [PubMed] [PMC]
20. Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185(14):2401-2421.

[DOI] [PubMed] [PMC]
21. Kagan VE, Mao G, Qu F, Angeli JPF, Doll S, St Croix C, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13(1):81-90.

[DOI] [PubMed] [PMC]
22. Mashayekhi S, Majedi H, Dehpour AR, Dehghan S, Jafarian M, Hadjighassem M, et al. Ferroptosis as a therapeutic target in glioblastoma: Mechanisms and emerging strategies. Mol Ther Nucleic Acids. 2025;36(3):102649.

[DOI] [PubMed] [PMC]
23. Sun H, Zhang J, Qi H, Jiang D, Hu C, Mao C, et al. Ioning out glioblastoma: Ferroptosis mechanisms and therapeutic frontiers. Cell Death Discov. 2025;11(1):407.

[DOI] [PubMed] [PMC]
24. D’Aprile S, Denaro S, Lavoro A, Candido S, Giallongo S, Torrisi F, et al. Glioblastoma mesenchymal subtype enhances antioxidant defence to reduce susceptibility to ferroptosis. Sci Rep. 2024;14:20770.

[DOI] [PubMed] [PMC]
25. Liu T, Zhu C, Chen X, Guan G, Zou C, Shen S, et al. Ferroptosis, as the most enriched programmed cell death process in glioma, induces immunosuppression and immunotherapy resistance. Neuro Oncol. 2022;24(7):1113-1125.

[DOI] [PubMed] [PMC]
26. Cheng J, Fan YQ, Liu BH, Zhou H, Wang JM, Chen QX. ACSL4 suppresses glioma cells proliferation via activating ferroptosis. Oncol Rep. 2020;43(1):147-158.

[DOI] [PubMed] [PMC]
27. Cirotti C, Taddei I, Contadini C, di Girolamo C, Pepe G, De Bardi M, et al. NRF2 connects Src tyrosine kinase to ferroptosis resistance in glioblastoma. Life Sci Alliance. 2024;7(1):e202302205.

[DOI] [PubMed] [PMC]
28. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273-285.

[DOI] [PubMed] [PMC]
29. Magtanong L, Ko PJ, To M, Cao JY, Forcina GC, Tarangelo A, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol. 2019;26(3):420-432.e9.

[DOI] [PubMed] [PMC]
30. Li Z, Lange M, Dixon SJ, Olzmann JA. Lipid quality control and ferroptosis: From concept to mechanism. Annu Rev Biochem. 2024;93:499-528.

[DOI] [PubMed] [PMC]
31. Klett EL, Chen S, Yechoor A, Lih FB, Coleman RA. Long-chain acyl-CoA synthetase isoforms differ in preferences for eicosanoid species and long-chain fatty acids. J Lipid Res. 2017;58(5):884-894.

[DOI] [PubMed] [PMC]
32. Yuan H, Li X, Zhang X, Kang R, Tang D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478(3):1338-1343.

[DOI] [PubMed]
33. von Krusenstiern AN, Robson RN, Qian N, Qiu B, Hu F, Reznik E, et al. Identification of essential sites of lipid peroxidation in ferroptosis. Nat Chem Biol. 2023;19(6):719-730.

[DOI] [PubMed] [PMC]
34. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91-98.

[DOI] [PubMed] [PMC]
35. Bezawork-Geleta A, Dimou J, Watt MJ. Lipid droplets and ferroptosis as new players in brain cancer glioblastoma progression and therapeutic resistance. Front Oncol. 2022;12:1085034.

[DOI] [PubMed] [PMC]
36. Kim JW, Lee JY, Oh M, Lee EW. An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis. Exp Mol Med. 2023;55(8):1620-1631.

[DOI] [PubMed] [PMC]
37. Pan D, Jiao M, Zhu Y, Hu M, Li F, Yu J, et al. DGAT1 inhibition induces ferroptosis and enhances cancer immunotherapy efficacy. Cancer Res. 2026;86(12):3026-3039.

[DOI] [PubMed] [PMC]
38. Cheng X, Geng F, Pan M, Wu X, Zhong Y, Wang C, et al. Targeting DGAT1 ameliorates glioblastoma by increasing fat catabolism and oxidative stress. Cell Metab. 2020;32(2):229-242.e8.

[DOI] [PubMed] [PMC]
39. Geng F, Guo D. Lipid droplets, potential biomarker and metabolic target in glioblastoma. Intern Med Rev. 2017.

[DOI] [PubMed] [PMC]
40. Wu X, Geng F, Cheng X, Guo Q, Zhong Y, Cloughesy TF, et al. Lipid droplets maintain energy homeostasis and glioblastoma growth via autophagic release of stored fatty acids. iScience. 2020;23(10):101569.

[DOI] [PubMed] [PMC]
41. Puca F, Yu F, Bartolacci C, Pettazzoni P, Carugo A, Huang-Hobbs E, et al. Medium-chain acyl-CoA dehydrogenase protects mitochondria from lipid peroxidation in glioblastoma. Cancer Discov. 2021;11(11):2904-2923.

[DOI] [PubMed] [PMC]
42. Yan Y, Teng H, Hang Q, Kondiparthi L, Lei G, Horbath A, et al. SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells. Nat Commun. 2023;14(1):3673.

[DOI] [PubMed] [PMC]
43. Sato H, Tamba M, Ishii T, Bannai S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem. 1999;274(17):11455-11458.

[DOI] [PubMed]
44. Polewski MD, Reveron-Thornton RF, Cherryholmes GA, Marinov GK, Aboody KS. SLC7A11 overexpression in glioblastoma is associated with increased cancer stem cell-like properties. Stem Cells Dev. 2017;26(17):1236-1246.

[DOI] [PubMed] [PMC]
45. Polewski MD, Reveron-Thornton RF, Cherryholmes GA, Marinov GK, Cassady K, Aboody KS. Increased expression of system xc- in glioblastoma confers an altered metabolic state and temozolomide resistance. Mol Cancer Res. 2016;14(12):1229-1242.

[DOI] [PubMed] [PMC]
46. Tarangelo A, Magtanong L, Bieging-Rolett KT, Li Y, Ye J, Attardi LD, et al. p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep. 2018;22(3):569-575.

[DOI] [PubMed] [PMC]
47. Boukalova S, Hubackova S, Milosevic M, Ezrova Z, Neuzil J, Rohlena J. Dihydroorotate dehydrogenase in oxidative phosphorylation and cancer. Biochim Biophys Acta BBA Mol Basis Dis. 2020;1866(6):165759.

[DOI] [PubMed]
48. Barnes T, Parry P, Hart I, Jones C, Minet M, Patterson D. Regional mapping of the gene encoding dihydroorotate dehydrogenase, an enzyme involved in UMP synthesis, electron transport, and superoxide generation, to human chromosome region 16q22. Somat Cell Mol Genet. 1993;19(4):405-411.

[DOI] [PubMed]
49. Schild T, Keshari KR. Revealing de novo pyrimidine synthesis as a key vulnerability in brain tumors. Cancer Cell. 2022;40(12):1457-1458.

[DOI] [PubMed]
50. Spina R, Mills I, Ahmad F, Chen C, Ames HM, Winkles JA, et al. DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts. Oncogene. 2022;41(50):5361-5372.

[DOI] [PubMed] [PMC]
51. Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593(7860):586-590.

[DOI] [PubMed] [PMC]
52. Mishima E, Nakamura T, Zheng J, Zhang W, Santos Dias Mourão A, Sennhenn P, et al. DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature. 2023;619(7968):E9-E18.

[DOI] [PubMed]
53. Miao Z, Xu L, Gu W, Ren Y, Li R, Zhang S, et al. A targetable PRR11-DHODH axis drives ferroptosis- and temozolomide-resistance in glioblastoma. Redox Biol. 2024;73:103220.

[DOI] [PubMed] [PMC]
54. Li K, Chen B, Xu A, Shen J, Li K, Hao K, et al. TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells. Redox Biol. 2022;56:102451.

[DOI] [PubMed] [PMC]
55. Huan X, Li J, Chu Z, Zhang H, Cheng L, Lun P, et al. Dysregulation of iron homeostasis mediated by FTH increases ferroptosis sensitivity in TP53-mutant glioblastoma. Neurosci Bull. 2025;41(4):569-582.

[DOI] [PubMed] [PMC]
56. Deshmukh P, Unni S, Krishnappa G, Padmanabhan B. The Keap1-Nrf2 pathway: Promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophys Rev. 2017;9(1):41-56.

[DOI] [PubMed] [PMC]
57. Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta BBA Mol Cell Res. 2018;1865(5):721-733.

[DOI] [PubMed]
58. Yu C, Xiao JH. The Keap1-Nrf2 system: A mediator between oxidative stress and aging. Oxid Med Cell Longev. 2021;2021:6635460.

[DOI] [PubMed] [PMC]
59. Fan Z, Wirth AK, Chen D, Wruck CJ, Rauh M, Buchfelder M, et al. Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis. 2017;6(8):e371.

[DOI] [PubMed] [PMC]
60. Wei Y, Duan S, Gong F, Li Q. The RNA-binding protein fragile-X mental retardation autosomal 1 (FXR1) modulates glioma cells sensitivity to temozolomide by regulating ferroptosis. Biochem Biophys Res Commun. 2022;603:153-159.

[DOI] [PubMed]
61. Sun S, Gao T, Pang B, Su X, Guo C, Zhang R, et al. RNA binding protein NKAP protects glioblastoma cells from ferroptosis by promoting SLC7A11 mRNA splicing in an m⁶A-dependent manner. Cell Death Dis. 2022;13(1):73.

[DOI] [PubMed] [PMC]
62. Sun Q, Lu H, Yuan FE, Zhao Q, Wei Y, Wang R, et al. SLC10A3 regulates ferroptosis of glioblastoma through the STAT3/GPX4 pathway. Sci Rep. 2025;15(1):21259.

[DOI] [PubMed] [PMC]
63. Zheng X, Toyama T, Siu S, Kaneko T, Sugiura H, Yamashita S, et al. Selenoprotein P expression in glioblastoma as a regulator of ferroptosis sensitivity: Preservation of GPX4 via the cycling-selenium storage. Sci Rep. 2024;14:682.

[DOI] [PubMed] [PMC]
64. Felsberg J, Hentschel B, Kaulich K, Gramatzki D, Zacher A, Malzkorn B, et al. Epidermal growth factor receptor variant III (EGFRvIII) positivity in EGFR-amplified glioblastomas: Prognostic role and comparison between primary and recurrent tumors. Clin Cancer Res. 2017;23(22):6846-6855.

[DOI] [PubMed]
65. Lv D, Zhong C, Dixit D, Yang K, Wu Q, Godugu B, et al. EGFR promotes ALKBH5 nuclear retention to attenuate N6-methyladenosine and protect against ferroptosis in glioblastoma. Mol Cell. 2023;83(23):4334-4351.e7.

[DOI] [PubMed] [PMC]
66. Benitez JA, Ma J, D’Antonio M, Boyer A, Camargo MF, Zanca C, et al. PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3. Nat Commun. 2017;8:15223.

[DOI] [PubMed] [PMC]
67. Georgescu MM. PTEN tumor suppressor network in PI3K-Akt pathway control. Genes Cancer. 2010;1(12):1170-1177.

[DOI] [PubMed] [PMC]
68. Cahuzac KM, Lubin A, Bosch K, Stokes N, Shoenfeld SM, Zhou R, et al. AKT activation because of PTEN loss upregulates xCT via GSK3β/NRF2, leading to inhibition of ferroptosis in PTEN-mutant tumor cells. Cell Rep. 2023;42(5):112536.

[DOI] [PubMed] [PMC]
69. Cai J, Ye Z, Hu Y, Ye L, Gao L, Wang Y, et al. Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. Cell Death Dis. 2023;14:211.

[DOI] [PubMed] [PMC]
70. Pirozzi CJ, Hai Y. The implications of IDH mutations for cancer development and therapy. Nat Rev Clin Oncol. 2021;18(10):645-661.

[DOI] [PubMed]
71. Han S, Liu Y, Cai SJ, Qian M, Ding J, Larion M, et al. IDH mutation in glioma: Molecular mechanisms and potential therapeutic targets. Br J Cancer. 2020;122(11):1580-1589.

[DOI] [PubMed] [PMC]
72. Badur MG, Muthusamy T, Parker SJ, Ma S, McBrayer SK, Cordes T, et al. Oncogenic R132 IDH1 mutations limit NADPH for de novo lipogenesis through (D)₂-hydroxyglutarate production in fibrosarcoma cells. Cell Rep. 2018;25(6):1680.

[DOI] [PubMed] [PMC]
73. Wang TX, Liang JY, Zhang C, Xiong Y, Guan KL, Yuan HX. The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis. Cell Death Dis. 2019;10(10):755.

[DOI] [PubMed] [PMC]
74. Liu Y, Chou FJ, Lang F, Zhang M, Song H, Zhang W, et al. Protein kinase B (PKB/AKT) protects IDH-mutated glioma from ferroptosis via Nrf2. Clin Cancer Res. 2023;29(7):1305-1316.

[DOI] [PubMed] [PMC]
75. Sahu U, Mullarkey MP, Murphy SA, Anderson JC, Putluri V, Kamal AHM, et al. IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity. Nat Commun. 2025;16(1):3874.

[DOI] [PubMed] [PMC]
76. Bhaduri A, di Lullo E, Jung D, Müller S, Crouch EE, Espinosa CS, et al. Outer radial glia-like cancer stem cells contribute to heterogeneity of glioblastoma. Cell Stem Cell. 2020;26(1):48-63.e6.

[DOI] [PubMed] [PMC]
77. Yabo YA, Niclou SP, Golebiewska A. Cancer cell heterogeneity and plasticity: A paradigm shift in glioblastoma. Neuro Oncol. 2022;24(5):669-682.

[DOI] [PubMed] [PMC]
78. Pine AR, Cirigliano SM, Nicholson JG, Hu Y, Linkous A, Miyaguchi K, et al. Tumor microenvironment is critical for the maintenance of cellular states found in primary glioblastomas. Cancer Discov. 2020;10(7):964-979.

[DOI] [PubMed] [PMC]
79. Vo VTA, Kim S, Hua TNM, Oh J, Jeong Y. Iron commensalism of mesenchymal glioblastoma promotes ferroptosis susceptibility upon dopamine treatment. Commun Biol. 2022;5(1):593.

[DOI] [PubMed] [PMC]
80. Banu MA, Dovas A, Argenziano MG, Zhao W, Sperring CP, Cuervo Grajal H, et al. A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma. EMBO J. 2024;43(20):4492-4521.

[DOI] [PubMed] [PMC]
81. Mbah NE, Myers AL, Sajjakulnukit P, Chung C, Thompson JK, Hong HS, et al. Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma. Nat Commun. 2024;15(1):8983.

[DOI] [PubMed] [PMC]
82. Bou-Gharios J, Noël G, Burckel H. Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme. Cell Death Dis. 2024;15(7):503.

[DOI] [PubMed] [PMC]
83. Bayona C, Ranđelović T, Ochoa I. Tumor microenvironment in glioblastoma: The central role of the hypoxic-necrotic core. Cancer Lett. 2026;639:218216.

[DOI] [PubMed]
84. Feldman L. Hypoxia within the glioblastoma tumor microenvironment: A master saboteur of novel treatments. Front Immunol. 2024;15:1384249.

[DOI] [PubMed] [PMC]
85. Sun S, Guo C, Gao T, Ma D, Su X, Pang Q, et al. Hypoxia enhances glioma resistance to sulfasalazine-induced ferroptosis by upregulating SLC7A11 via PI3K/AKT/HIF-1α axis. Oxid Med Cell Longev. 2022;2022:7862430.

[DOI] [PubMed] [PMC]
86. Chen N, Hao C, Peng X, Lin H, Yin A, Hao L, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019;381(11):1001-1010.

[DOI] [PubMed]
87. Su X, Xie Y, Zhang J, Li M, Zhang Q, Jin G, et al. HIF-α activation by the prolyl hydroxylase inhibitor roxadustat suppresses chemoresistant glioblastoma growth by inducing ferroptosis. Cell Death Dis. 2022;13(10):861.

[DOI] [PubMed] [PMC]
88. Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20-27.

[DOI] [PubMed] [PMC]
89. Chen Z, Feng X, Herting CJ, Garcia VA, Nie K, Pong WW, et al. Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res. 2017;77(9):2266-2278.

[DOI] [PubMed] [PMC]
90. Xu X, Zhang Y, Liao C, Zhou H, Wu Y, Zhang W. Impact of ferroptosis-related risk genes on macrophage M1/M2 polarization and prognosis in glioblastoma. Front Cell Neurosci. 2023;17:1294029.

[DOI] [PubMed] [PMC]
91. Hosseinalizadeh H, Mahmoodpour M, Samadani AA, Roudkenar MH. The immunosuppressive role of indoleamine 2, 3-dioxygenase in glioblastoma: Mechanism of action and immunotherapeutic strategies. Med Oncol. 2022;39(9):130.

[DOI] [PubMed] [PMC]
92. Tian Q, Dan G, Wang X, Zhu J, Chen C, Tang D, et al. IDO1 inhibits ferroptosis by regulating FTO-mediated M6A methylation and SLC7A11 mRNA stability during glioblastoma progression. Cell Death Discov. 2025;11(1):22.

[DOI] [PubMed] [PMC]
93. Jung KH, LoRusso P, Burris H, Gordon M, Bang YJ, Hellmann MD, et al. Phase I study of the indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) administered with PD-L1 inhibitor (atezolizumab) in advanced solid tumors. Clin Cancer Res. 2019;25(11):3220-3228.

[DOI] [PubMed] [PMC]
94. Naing A, Eder JP, Piha-Paul SA, Gimmi C, Hussey E, Zhang S, et al. Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2, 3-dioxygenase 1 and tryptophan 2, 3-dioxygenase 2, in patients with advanced solid tumors. J Immunother Cancer. 2020;8(2):e000870.

[DOI] [PubMed] [PMC]
95. Gao M, Yu W, Xi Z, Zhang Z, Fan X, Wang X. Recent update on the discovery of indoleamine-2, 3-dioxygenase 1 inhibitors targeting cancer immunotherapy. Eur J Med Chem. 2025;298:118017.

[DOI] [PubMed]
96. Sahu AP, Palsa K, Shenoy G, Slagle-Webb B, Connor JR. Tumor-associated macrophages promote ferroptosis resistance in glioblastoma by stimulating iron-loaded extracellular vesicle release. J Neurooncol. 2026;177(2):99.

[DOI] [PubMed] [PMC]
97. Schwantes A, Shadid Y, Guerrero Ruiz VM, Aliraj B, Wickert A, Palmer MA, et al. Ferroptosis enhances T lymphocyte infiltration into glioblastoma spheroids. Antioxidants (Basel). 2025;14(11):1373.

[DOI] [PubMed] [PMC]
98. Ye LF, Chaudhary KR, Zandkarimi F, Harken AD, Kinslow CJ, Upadhyayula PS, et al. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem Biol. 2020;15(2):469-484.

[DOI] [PubMed] [PMC]
99. Song Q, Peng S, Sun Z, Heng X, Zhu X. Temozolomide drives ferroptosis via a DMT1-dependent pathway in glioblastoma cells. Yonsei Med J. 2021;62(9):843-849.

[DOI] [PubMed] [PMC]
100. Yang H, Zhao W, Huang Y, Wu Y, Zou Y, Wang T, et al. Novel imidazotetrazine derivatives overcome temozolomide resistance in glioblastoma by inducing ferroptosis and apoptosis. Cell Death Discov. 2026;12:14.

[DOI] [PubMed] [PMC]
101. Jezierzański M, Nafalska N, Stopyra M, Furgoł T, Miciak M, Kabut J, et al. Temozolomide (TMZ) in the treatment of glioblastoma multiforme-a literature review and clinical outcomes. Curr Oncol. 2024;31(7):3994-4002.

[DOI] [PubMed] [PMC]
102. Wang J, Guo D, Jiang S, Wu W, Gao X. Targeting ferroptosis in cancer: From mechanistic insights to therapeutic approaches. Mol Biomed. 2026;7(1):20.

[DOI] [PubMed] [PMC]
103. Caforio M, Iacovelli S, Locatelli F, Folgiero V. Inducing ferroptosis to improve cancer therapy: A promising tool for enhancing immunotherapy. J Exp Clin Cancer Res. 2025;45(1):10.

[DOI] [PubMed] [PMC]
104. Sun S, Shen J, Jiang J, Wang F, Min J. Targeting ferroptosis opens new avenues for the development of novel therapeutics. Sig Transduct Target Ther. 2023;8(1):372.

[DOI] [PubMed] [PMC]
105. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072.

[DOI] [PubMed] [PMC]
106. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1-2):317-331.

[DOI] [PubMed] [PMC]
107. Yu H, Guo P, Xie X, Wang Y, Chen G. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med. 2017;21(4):648-657.

[DOI] [PubMed] [PMC]
108. Robe PA, Martin DH, Nguyen-Khac MT, Artesi M, Deprez M, Albert A, et al. Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults. BMC Cancer. 2009;9:372.

[DOI] [PubMed] [PMC]
109. Wang L, Chen X, Yan C. Ferroptosis: An emerging therapeutic opportunity for cancer. Genes Dis. 2022;9(2):334-346.

[DOI] [PubMed] [PMC]
110. Hassannia B, Wiernicki B, Ingold I, Qu F, Van Herck S, Tyurina YY, et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest. 2018;128(8):3341-3355.

[DOI] [PubMed] [PMC]
111. Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016;12(7):497-503.

[DOI] [PubMed] [PMC]
112. Zhang X, Guo Y, Li H, Han L. FIN56, a novel ferroptosis inducer, triggers lysosomal membrane permeabilization in a TFEB-dependent manner in glioblastoma. J Cancer. 2021;12(22):6610-6619.

[DOI] [PubMed] [PMC]
113. Hambright WS, Fonseca RS, Chen L, Na R, Ran Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017;12:8-17.

[DOI] [PubMed] [PMC]
114. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16(12):1180-1191.

[DOI] [PubMed] [PMC]
115. Carlson BA, Tobe R, Yefremova E, Tsuji PA, Hoffmann VJ, Schweizer U, et al. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox Biol. 2016;9:22-31.

[DOI] [PubMed] [PMC]
116. Louandre C, Ezzoukhry Z, Godin C, Barbare JC, Mazière JC, Chauffert B, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer. 2013;133(7):1732-1742.

[DOI] [PubMed]
117. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390.

[DOI] [PubMed]
118. Zheng J, Sato M, Mishima E, Sato H, Proneth B, Conrad M. Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell Death Dis. 2021;12(7):698.

[DOI] [PubMed] [PMC]
119. Mortensen MS, Ruiz J, Watts JL. Polyunsaturated fatty acids drive lipid peroxidation during ferroptosis. Cells. 2023;12(5):804.

[DOI] [PubMed] [PMC]
120. Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 2015;10(7):1604-1609.

[DOI] [PubMed] [PMC]
121. Cao J, Chen X, Chen L, Lu Y, Wu Y, Deng A, et al. DHODH-mediated mitochondrial redox homeostasis: A novel ferroptosis regulator and promising therapeutic target. Redox Biol. 2025;85:103788.

[DOI] [PubMed] [PMC]
122. Teng D, Swanson KD, Wang R, Zhuang A, Wu H, Niu Z, et al. DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis. Nat Commun. 2025;16(1):3867.

[DOI] [PubMed] [PMC]
123. Olsen TK, Dyberg C, Embaie BT, Alchahin A, Milosevic J, Ding J, et al. DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma. JCI Insight. 2022;7(17):e153836.

[DOI] [PubMed] [PMC]
124. Cao Z, Liu X, Zhang W, Zhang K, Pan L, Zhu M, et al. Biomimetic macrophage membrane-camouflaged nanoparticles induce ferroptosis by promoting mitochondrial damage in glioblastoma. ACS Nano. 2023;17(23):23746-23760.

[DOI] [PubMed] [PMC]
125. Li LC, Okino ST, Zhao H, Pookot D, Place RF, Urakami S, et al. Small dsRNAs induce transcriptional activation in human cells. Proc Natl Acad Sci U S A. 2006;103(46):17337-17342.

[DOI] [PubMed] [PMC]
126. Meng X, Jiang Q, Chang N, Wang X, Liu C, Xiong J, et al. Small activating RNA binds to the genomic target site in a seed-region-dependent manner. Nucleic Acids Res. 2016;44(5):2274-2282.

[DOI] [PubMed] [PMC]
127. Li B, Chen X, Qiu W, Zhao R, Duan J, Zhang S, et al. Synchronous disintegration of ferroptosis defense axis via engineered exosome-conjugated magnetic nanoparticles for glioblastoma therapy. Adv Sci (Weinh). 2022;9(17):e2105451.

[DOI] [PubMed] [PMC]
128. Liu B, Ji Q, Cheng Y, Liu M, Zhang B, Mei Q, et al. Biomimetic GBM-targeted drug delivery system boosting ferroptosis for immunotherapy of orthotopic drug-resistant GBM. J Nanobiotechnology. 2022;20(1):161.

[DOI] [PubMed] [PMC]
129. Ge Z, Wang Z, Zhao E, Guo Y, Zhang L, Tian F, et al. Stress granules restrain ferroptosis by sequestering ferritin. Nat Cell Biol. 2026;28(6):1204-1218.

[DOI] [PubMed]
130. Chen C, Zhu X, Song Z, Xing Y, Jin W, Li F, et al. Dual-targeted bacterial outer membrane vesicles enhance glioblastoma immunotherapy by regulating tumor microenvironment and inducing IFN-γ-mediated ferroptosis. J Nanobiotechnology. 2025;24(1):44.

[DOI] [PubMed] [PMC]
131. Wang X, Shi W, Li M, Xin Y, Jiang X. RSL3 sensitizes glioma cells to ionizing radiation by suppressing TGM2-dependent DNA damage repair and epithelial-mesenchymal transition. Redox Biol. 2024;78:103438.

[DOI] [PubMed] [PMC]
132. Zhu X, Zhou Y, Ou Y, Cheng Z, Han D, Chu Z, et al. Characterization of ferroptosis signature to evaluate the predict prognosis and immunotherapy in glioblastoma. Aging. 2021;13(13):17655-17672.

[DOI] [PubMed] [PMC]
133. Luo Y, Bai XY, Zhang L, Hu QQ, Zhang N, Cheng JZ, et al. Ferroptosis in cancer therapy: Mechanisms, small molecule inducers, and novel approaches. Drug Des Devel Ther. 2024;18:2485-2529.

[DOI] [PubMed] [PMC]
134. Jiang T, Ma W, Dong W, Zhou H, Mao X. Ferroptosis-associated transcriptional factors in neurological diseases: Molecular mechanisms and therapeutic prospects. Exp Mol Med. 2025;57(12):2763-2781.

[DOI] [PubMed] [PMC]
135. Huang Q, Zhang H, Chen S, Wang Y, Zhou J. Ferroptosis in central nervous system injuries: Molecular mechanisms, diagnostic approaches, and therapeutic strategies. Front Cell Neurosci. 2025;19:1593963.

[DOI] [PubMed] [PMC]
136. Wei Z, Yu H, Zhao H, Wei M, Xing H, Pei J, et al. Broadening horizons: Ferroptosis as a new target for traumatic brain injury. Burns Trauma. 2024;12:tkad051.

[DOI] [PubMed] [PMC]
137. Liu Q, Song T, Chen B, Zhang J, Li W. Ferroptosis of brain microvascular endothelial cells contributes to hypoxia-induced blood-brain barrier injury. FASEB J. 2023;37(5):e22874.

[DOI] [PubMed]
138. Chen L, Hambright WS, Na R, Ran Q. Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem. 2015;290(47):28097-28106.

[DOI] [PubMed] [PMC]
139. Mahoney-Sanchez L, Bouchaoui H, Boussaad I, Jonneaux A, Timmerman K, Berdeaux O, et al. Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition. Cell Rep. 2022;40(8):111231.

[DOI] [PubMed]
140. Vásquez V, Krieg M, Lockhead D, Goodman MB. Phospholipids that contain polyunsaturated fatty acids enhance neuronal cell mechanics and touch sensation. Cell Rep. 2014;6(1):70-80.

[DOI] [PubMed] [PMC]
141. Morita S, Kondo T, Tokuda H, Kaneda Y, Izumo T, Nakao Y, et al. Polyunsaturated fatty acids in lipid membranes regulate human neuronal function and amyloid-β production. iScience. 2025;28(6):112557.

[DOI] [PubMed] [PMC]
142. Mosele F, Peltier A, Ozaki Y, Detappe A, Soria JC, André F. The next generation of antibody-drug conjugates. Nat Med. 2026;32(8):2774-2785.

[DOI] [PubMed]
143. Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: The “biological missile” for targeted cancer therapy. Sig Transduct Target Ther. 2022;7:93.

[DOI] [PubMed] [PMC]
144. Fan R, Chen C, Mu M, Chuan D, Liu H, Hou H, et al. Engineering MMP-2 activated nanoparticles carrying B7-H3 bispecific antibodies for ferroptosis-enhanced glioblastoma immunotherapy. ACS Nano. 2023;17(10):9126-9139.

[DOI] [PubMed]
145. Zhang Y, Chi X, Feng R, Xian N, Huang N, Sun S, et al. Intracranial delivery of B7-H3-targeting CAR-T cells for recurrent glioblastoma: A phase 1 trial. Nat Med. 2026;32(9):3268-3275.

[DOI] [PubMed]
146. Martins TA, Kaymak D, Tatari N, Gerster F, Hogan S, Ritz MF, et al. Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker. Nat Commun. 2024;15(1):9718.

[DOI] [PubMed] [PMC]
147. Hamblett KJ, Kozlosky CJ, Siu S, Chang WS, Liu H, Foltz IN, et al. AMG 595, an anti-EGFRvIII antibody-drug conjugate, induces potent antitumor activity against EGFRvIII-expressing glioblastoma. Mol Cancer Ther. 2015;14(7):1614-1624.

[DOI] [PubMed]
148. Rosenthal M, Curry R, Reardon DA, Rasmussen E, Upreti VV, Damore MA, et al. Safety, tolerability, and pharmacokinetics of anti-EGFRvIII antibody-drug conjugate AMG 595 in patients with recurrent malignant glioma expressing EGFRvIII. Cancer Chemother Pharmacol. 2019;84(2):327-336.

[DOI] [PubMed]
149. van den Bent M, Gan HK, Lassman AB, Kumthekar P, Merrell R, Butowski N, et al. Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: Results from a multi-center, international study. Cancer Chemother Pharmacol. 2017;80(6):1209-1217.

[DOI] [PubMed] [PMC]
150. Lassman AB, van den Bent MJ, Gan HK, Reardon DA, Kumthekar P, Butowski N, et al. Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: Results from an international phase I multicenter trial. Neuro Oncol. 2019;21(1):106-114.

[DOI] [PubMed] [PMC]
151. Clement PMJ, Dirven L, Eoli M, Sepulveda-Sanchez JM, Walenkamp AME, Frenel JS, et al. Impact of depatuxizumab mafodotin on health-related quality of life and neurological functioning in the phase II EORTC 1410/INTELLANCE 2 trial for EGFR-amplified recurrent glioblastoma. Eur J Cancer. 2021;147:1-12.

[DOI] [PubMed]
152. Nguyen KA, Conilh L, Falson P, Dumontet C, Boumendjel A. The first ADC bearing the ferroptosis inducer RSL3 as a payload with conservation of the fragile electrophilic warhead. Eur J Med Chem. 2022;244:114863.

[DOI] [PubMed]
153. Zhang Y, Cui X, Du J, Cui G, Ling Y, Tang C. Development of the FGFR4-ADC bearing the ferroptosis inducer sulfasalazine for hepatocellular carcinoma. iScience. 2025;28(11):113718.

[DOI] [PubMed] [PMC]
154. Zhang Y, Du J, Cui X, Ling Y, Tang C. Development of a bispecific CDH17-GUCY2C ADC bearing the ferroptosis inducer RSL3 for the treatment of colorectal cancer. Cell Death Discov. 2025;11(1):347.

[DOI] [PubMed] [PMC]
155. Leak L, Dixon SJ. Surveying the landscape of emerging and understudied cell death mechanisms. Biochim Biophys Acta Mol Cell Res. 2023;1870(3):119432.

[DOI] [PubMed] [PMC]
156. Leak L, Wang Z, Joseph AJ, Johnson B, Chan AA, Decosto CM, et al. Tegavivint triggers TECR-dependent nonapoptotic cancer cell death. Nat Chem Biol. 2025;21(12):1873-1884.

[DOI] [PubMed] [PMC]

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Minami JK, Salinas JJ, Loo CE, Lee WC, Dixon SJ, Nathanson DA. Beyond frroptosis induction: Defining ferroptosis vulnerability in glioblastoma. Ferroptosis Oxid Stress. 2027;3:202637. https://doi.org/10.70401/fos.2026.0048

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Ferroptosis and Oxidative Stress

Beyond frroptosis induction: Defining ferroptosis vulnerability in glioblastoma

Jenna K Minami

Jennifer J Salinas

Caitlyn E Loo

Weaverly Colleen Lee

Scott J Dixon

David A Nathanson

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Ferroptosis and Oxidative Stress

Beyond frroptosis induction: Defining ferroptosis vulnerability in glioblastoma

Jenna K Minami

Jennifer J Salinas

Caitlyn E Loo

Weaverly Colleen Lee

Scott J Dixon

David A Nathanson

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