A fistful of iron: ferritin as a vulnerability point of the brain cancers

1. Chen Y, Fan Z, Yang Y, Gu C. Iron metabolism and its contribution to cancer (Review). Int J Oncol. 2019. http://www.spandidos-publications.com/10.3892/ijo.2019.4720

2. Rodriguez R, Schreiber SL, Conrad M. Persister cancer cells: Iron addiction and vulnerability to ferroptosis. Mol Cell. 2022;82:728–40.

   Google Scholar 

3. Schonberg DL, Miller TE, Wu Q, Flavahan WA, Das NK, Hale JS, et al. Preferential iron trafficking characterizes glioblastoma stem-like cells. Cancer Cell. 2015;28:441–55.

   Google Scholar 

4. 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;149:1060–72.

   Google Scholar 

5. Fenton HJH. Oxidation of tartaric acid in presence of iron. University of Windsor. 1894. p. 11.

6. Zhu ZY, Liu YD, Gong Y, Jin W, Topchiy E, Turdi S, et al. Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer’s disease via inhibition of ACSL4-dependent ferroptosis. Acta Pharmacol Sin. 2022;43:39–49.

   Google Scholar 

7. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26:165–76.

   Google Scholar 

8. 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;19:719–30.

   Google Scholar 

9. Wang P, Yao Q, Zhu D, Yang X, Chen Q, Lu Q, et al. Resveratrol protects against deoxynivalenol-induced ferroptosis in HepG2 cells. Toxicology. 2023;494:153589.

   Google Scholar 

10. Geng N, Shi B-J, Li S-L, Zhong Z-Y, Li Y-C, Xua W-L, et al. Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. Eur Rev Med Pharmacol Sci. 2018;22:3826–36.

11. Dolma S, Lessnick SL, Hahn WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003;3:285–96.

    Google Scholar 

12. Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15:234–45.

    Google Scholar 

13. Mo Q, Song C, Hua Y, Wang W, Liu A. CYP2E1 mediated deoxynivalenol-induced hepatocyte toxicity by regulating ferroptosis. Toxicology. 2024;508:153923.

    Google Scholar 

14. Zhou X, Wang H, Yan B, Nie X, Chen Q, Yang X, et al. Ferroptosis in cardiovascular diseases and ferroptosis-related intervention approaches. Cardiovasc Drugs Ther. 2024. https://link.springer.com/10.1007/s10557-024-07642-5.

15. Ibrahim O, O’Sullivan J. Iron chelators in cancer therapy. BioMetals. 2020;33:201–15.

    Google Scholar 

16. Wallace DF. The regulation of iron absorption and homeostasis. Clin Biochem Rev. 2016;37:51–62.

17. Gao T, O’Brian MR. Iron-dependent cytochrome c ₁ expression is mediated by the status of heme in Bradyrhizobium japonicum. J Bacteriol. 2005;187:5084–9.

    Google Scholar 

18. Mühlenhoff U, Richhardt N, Gerber J, Lill R. Characterization of iron–sulfur protein assembly in isolated mitochondria. J Biol Chem. 2002;277:29810–6.

    Google Scholar 

19. Read AD, Bentley RE, Archer SL, Dunham-Snary KJ. Mitochondrial iron–sulfur clusters: structure, function, and an emerging role in vascular biology. Redox Biol. 2021;47:102164.

    Google Scholar 

20. Rangaraju V, Calloway N, Ryan TA. Activity-driven kocal ATP synthesis is required for synaptic function. Cell. 2014;156:825–35.

    Google Scholar 

21. Pathak D, Shields LY, Mendelsohn BA, Haddad D, Lin W, Gerencser AA, et al. The role of mitochondrially derived ATP in synaptic vesicle recycling. J Biol Chem. 2015;290:22325–36.

    Google Scholar 

22. Van Bergen JMG, Li X, Hua J, Schreiner SJ, Steininger SC, Quevenco FC, et al. Colocalization of cerebral iron with amyloid beta in mild cognitive impairment. Sci Rep. 2016;6:35514.

    Google Scholar 

23. Yamamoto A, Shin R, Hasegawa K, Naiki H, Sato H, Yoshimasu F, et al. Iron (III) induces aggregation of hyperphosphorylated τ and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer’s disease. J Neurochem. 2002;82:1137–47.

    Google Scholar 

24. Kostka M, Högen T, Danzer KM, Levin J, Habeck M, Wirth A, et al. Single particle characterization of iron-induced pore-forming α-synuclein oligomers. J Biol Chem. 2008;283:10992–1003.

    Google Scholar 

25. Levin J, Högen T, Hillmer AS, Bader B, Schmidt F, Kamp F, et al. Generation of ferric iron links oxidative stress to α-synuclein oligomer formation. J Park Dis. 2011;1:205–16.

    Google Scholar 

26. Kumar N, Rizek P, Jog M. Neuroferritinopathy: pathophysiology, presentation, differential diagnoses and management. Tremor Hyperkinet Mov. 2016;6:355.

    Google Scholar 

27. Li Y, Guan Q, Chen Y, Han H, Liu W, Nie Z. Transferrin receptor and ferritin-H are developmentally regulated in oligodendrocyte lineage cells. Neural Regen Res. 2013;8:6.

    Google Scholar 

28. Chang S, Wang P, Han Y, Ma Q, Liu Z, Zhong S, et al. Ferrodifferentiation regulates neurodevelopment via ROS generation. Sci China Life Sci. 2023;66:1841–57.

    Google Scholar 

29. Pérez MJ, Carden TR, Dos Santos Claro PA, Silberstein S, Páez PM, Cheli VT, et al. Transferrin enhances neuronal differentiation. ASN Neuro. 2023;15:17590914231170703.

    Google Scholar 

30. Ma Z, Wang W, Yang X, Rui M, Wang S. Glial ferritin maintains neural stem cells via transporting iron required for self-renewal in Drosophila. Elife. 2024. https://elifesciences.org/reviewed-preprints/93604v2.

31. Ding Y, Yao S, Guo S, Meng W, Li J, Wang F, et al. Ferroportin 1 depletion in neural stem cells promotes hippocampal neurogenesis and cognitive function in mice. Pharmacol Res. 2025;216:107778.

    Google Scholar 

32. McCann S, Perapoch Amadó M, Moore SE. The role of iron in brain development: a systematic review. Nutrients. 2020;12:2001.

    Google Scholar 

33. Beard J. Iron deficiency alters brain development and functioning. J Nutr. 2003;133:1468S–1472S.

    Google Scholar 

34. Tang C, Yang J, Zhu C, Ding Y, Yang S, Xu B, et al. Iron metabolism disorder and multiple sclerosis: a comprehensive analysis. Front Immunol. 2024;15:1376838.

    Google Scholar 

35. Lawson DM, Treffry A, Artymiuk PJ, Harrison PM, Yewdall SJ, Luzzago A, et al. Identification of the ferroxidase centre in ferritin. FEBS Lett. 1989;254:207–10.

    Google Scholar 

36. Arosio P, Ingrassia R, Cavadini P. Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta BBA—Gen Subj. 2009;1790:589–99.

    Google Scholar 

37. Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer Sci. 2009;100:9–16.

    Google Scholar 

38. Nilsson R, Liu NA. Nuclear DNA damages generated by reactive oxygen molecules (ROS) under oxidative stress and their relevance to human cancers, including ionizing radiation-induced neoplasia part II: Relation between ROS-induced DNA damages and human cancer. Radiat Med Prot. 2020;1:196–204.

    Google Scholar 

39. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther. 2021;6:263.

    Google Scholar 

40. Zeidan RS, Yoon HS, Yang JJ, Sobh A, Braithwaite D, Mankowski R, et al. Iron and cancer: overview of the evidence from population-based studies. Front Oncol. 2024;14. https://www.frontiersin.org/articles/10.3389/fonc.2024.1393195/full.

41. Stevens RG, Jones DY, Micozzi MS, Taylor PR. Body iron stores and the risk of cancer. N Engl J Med. 1988;319:1047–52.

42. Selby JV, Friedman GD. Epidemiologic evidence of an association between body iron stores and risk of cancer. Int J Cancer. 1988;41:677–82.

    Google Scholar 

43. Stevens RG, Beasley P, Blumberg BS. Iron-binding proteins and risk of cancer in Taiwan. J Natl Cancer Inst. 1986;76:605–10.

44. Magnusson G, Flodh H, Malmfors T. Oncological Study in Rats of Ferastral®, an Iron–poly-(sorbitol-gluconic acid) complex, after Intramuscular administration. Scand J Haematol. 1977;19:87–98.

    Google Scholar 

45. Golberg L, Martin LE, Smith JP. Iron overloading phenomena in animals. Toxicol Appl Pharmacol. 1960;2:683–707.

    Google Scholar 

46. Shi X, Zhang A, Lu J, Wang X, Yi C, Yang F. An overview of heavy chain ferritin in cancer. Front Biosci-Landmark. 2023;28:182.

    Google Scholar 

47. Weinstein RE, Bond BH, Silberberg BK, Vaughn CB, Subbaiah P, Pieper DR. Tissue ferritin concentration and prognosis in carcinoma of the breast. Breast Cancer Res Treat. 1989;14:349–53.

    Google Scholar 

48. Ji M, Li XD, Shi HB, Ning ZH, Zhao WQ, Wang Q, et al. Clinical significance of serum ferritin in elderly patients with primary lung carcinoma. Tumor Biol. 2014;35:10195–9.

    Google Scholar 

49. Wang J, Liu QX, Teng DL, Ding YB, Lu GT, Gong WJ, et al. Elevated serum ferritin levels are associated with severity and prognosis of severe acute pancreatitis: a preliminary cohort study. BMC Gastroenterol. 2022;22:408.

    Google Scholar 

50. Feng Z, Chen JW, Feng JH, Shen F, Cai WS, Cao J, et al. The association between serum ferritin and colorectal cancer. Int J Clin Exp Med. 2015;8:22293–99.

51. Mortazavi H, Sabour S, Baharvand M, Manifar S, Akkafan R. Serum levels of ferritin, copper, and zinc in patients with oral cancer. Biomed J. 2014;37:331.

    Google Scholar 

52. Kalousová M, Krechler T, Jáchymová M, Kuběna AA, Žák A, Zima T. Ferritin as an independent mortality predictor in patients with pancreas cancer. Results of a pilot study. Tumor Biol. 2012;33:1695–700.

    Google Scholar 

53. Moroz V, Machin D, Hero B, Ladenstein R, Berthold F, Kao P, et al. The prognostic strength of serum LDH and serum ferritin in children with neuroblastoma: a report from the International Neuroblastoma Risk Group (INRG) project. Pediatr Blood Cancer. 2020;67:e28359.

    Google Scholar 

54. Wang X, An P, Zeng J, Liu X, Wang B, Fang X, et al. Serum ferritin in combination with prostate-specific antigen improves predictive accuracy for prostate cancer. Oncotarget. 2017;8:17862–72.

    Google Scholar 

55. Lorenzi M, Lorenzi B, Vernillo R. Serum ferritin in colorectal cancer patients and its prognostic evaluation. Int J Biol Markers. 2006;21:235–41.

56. Wu SJ, Zhang ZZ, Cheng NS, Xiong XZ, Yang L. Preoperative serum ferritin is an independent prognostic factor for liver cancer after hepatectomy. Surg Oncol. 2019;29:159–67.

    Google Scholar 

57. Wang SL, Cao S, Wu R, Chi F, Tang MY, Jin XY, et al. Serum ferritin predicted prognosis in patients with locally advanced pancreatic cancer. Future Oncol. 2015;11:2905–10.

    Google Scholar 

58. Rychtarcikova Z, Lettlova S, Tomkova V, Korenkova V, Langerova L, Simonova E, et al. Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism. Oncotarget. 2017;8:6376–98.

    Google Scholar 

59. Kindrat I, Tryndyak V, De Conti A, Shpyleva S, Mudalige TK, Kobets T, et al. MicroRNA-152-mediated dysregulation of hepatic transferrin receptor 1 in liver carcinogenesis. Oncotarget. 2016;7:1276–87.

    Google Scholar 

60. Basuli D, Tesfay L, Deng Z, Paul B, Yamamoto Y, Ning G, et al. Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene. 2017;36:4089–99.

    Google Scholar 

61. Wang B, Zhang J, Song F, Tian M, Shi B, Jiang H, et al. EGFR regulates iron homeostasis to promote cancer growth through redistribution of transferrin receptor 1. Cancer Lett. 2016;381:331–40.

    Google Scholar 

62. Xue X, Ramakrishnan SK, Weisz K, Triner D, Xie L, Attili D, et al. Iron uptake via DMT1 integrates cell cycle with JAK-STAT3 signaling to promote colorectal tumorigenesis. Cell Metab. 2016;24:447–61.

    Google Scholar 

63. Gu Z, Wang H, Xia J, Yang Y, Jin Z, Xu H, et al. Decreased ferroportin promotes myeloma cell growth and osteoclast differentiation. Cancer Res. 2015;75:2211–21.

    Google Scholar 

64. Feng G, Arima Y, Midorikawa K, Kobayashi H, Oikawa S, Zhao W, et al. Knockdown of TFRC suppressed the progression of nasopharyngeal carcinoma by downregulating the PI3K/Akt/mTOR pathway. Cancer Cell Int. 2023;23:185.

    Google Scholar 

65. Kim H, Villareal LB, Liu Z, Haneef M, Falcon DM, Martin DR, et al. Transferrin receptor-mediated iron uptake promotes colon tumorigenesis. Adv Sci. 2023;10:2207693.

    Google Scholar 

66. Hann HWL, Stahlhut MW, Menduke H. Iron enhances tumor growth. Observation on spontaneous mammary tumors in mice. Cancer. 1991;68:2407–10. Dec 1.

    Google Scholar 

67. Hann HW, Stahlhut MW, Blumberg BS. Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice. Cancer Res. 1988;48:4168–70.

68. Lui GYL, Obeidy P, Ford SJ, Tselepis C, Sharp DM, Jansson PJ, et al. The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action. Mol Pharmacol. 2013;83:179–90.

    Google Scholar 

69. White S, Taetle R, Seligman PA, Rutherford M, Trowbridge IS. Combinations of anti-transferrin receptor monoclonal antibodies inhibit human tumor cell growth in vitro and in vivo: evidence for synergistic antiproliferative effects. Cancer Res. 1990;50:6295–301.

70. Belvin BR, Lewis JP. Ferroportin depletes iron needed for cell cycle progression in head and neck squamous cell carcinoma. Front Oncol. 2023;12:1025434.

    Google Scholar 

71. Tian T, Li X, Zhang J. mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int J Mol Sci. 2019;20:755.

    Google Scholar 

72. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.

    Google Scholar 

73. Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA. 2002;99:13571–6.

    Google Scholar 

74. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–76.

    Google Scholar 

75. Shang C, Zhou H, Liu W, Shen T, Luo Y, Huang S. Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways. Oncogene. 2020;39:5201–13.

    Google Scholar 

76. Kim DH, Kim JH, Kim EH, Na HK, Cha YN, Chung JH, et al. 15-Deoxy-Δ 12,14 -prostaglandin J 2 upregulates the expression of heme oxygenase-1 and subsequently matrix metalloproteinase-1 in human breast cancer cells: possible roles of iron and ROS. Carcinogenesis. 2009;30:645–54.

    Google Scholar 

77. Cheng M, Liu P, Xu LX. Iron promotes breast cancer cell migration via IL-6/JAK2/STAT3 signaling pathways in a paracrine or autocrine IL-6-rich inflammatory environment. J Inorg Biochem. 2020;210:111159.

    Google Scholar 

78. Mehta KJ, Sharp PA. Iron elevates mesenchymal and metastatic biomarkers in HepG2 cells. Sci Rep. 2020;10:21926.

    Google Scholar 

79. Bhutia YD, Ogura J, Grippo PJ, Torres C, Sato T, Wachtel M, et al. Chronic exposure to excess iron promotes EMT and cancer via p53 loss in pancreatic cancer. Asian J Pharm Sci. 2020;15:237–51.

    Google Scholar 

80. Chen Z, Zhang D, Yue F, Zheng M, Kovacevic Z, Richardson DR. The Iron Chelators Dp44mT and DFO inhibit TGF-β-induced epithelial–mesenchymal transition via up-regulation of N-Myc downstream-regulated gene 1 (NDRG1). J Biol Chem. 2012;287:17016–28.

    Google Scholar 

81. Le NTV, Richardson DR. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation. Blood. 2004;104:2967–75.

    Google Scholar 

82. Oft M, Heider KH, Beug H. TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol. 1998;8:1243–52.

    Google Scholar 

83. Recalcati S, Locati M, Marini A, Santambrogio P, Zaninotto F, De Pizzol M, et al. Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol. 2010;40:824–35.

    Google Scholar 

84. Li H, Yang C, Wei Y, Li X, Jiang W, Xu Y, et al. Ferritin light chain promotes the reprogramming of glioma immune microenvironment and facilitates glioma progression. Theranostics. 2023;13:3794–813.

    Google Scholar 

85. Ermakov MS, Nushtaeva AA, Richter VA, Koval OA. Cancer-associated fibroblasts and their role in tumor progression. Vavilov J Genet Breed. 2022;26:14–21.

    Google Scholar 

86. Zhang K, Liu K, Hu B, Du G, Chen X, Xiao L, et al. Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer. Nat Commun. 2024;15:9050.

    Google Scholar 

87. Parks SK, Cormerais Y, Pouysségur J. Hypoxia and cellular metabolism in tumour pathophysiology. J Physiol. 2017;595:2439–50.

    Google Scholar 

88. Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13:342–55.

    Google Scholar 

89. Kaelin WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.

    Google Scholar 

90. Eckard J, Dai J, Wu J, Jian J, Yang Q, Chen H, et al. Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Cancer Cell Int. 2010;10:28.

    Google Scholar 

91. Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell. 2015;16:225–38.

    Google Scholar 

92. Zhang Q, Han Z, Zhu Y, Chen J, Li W. Role of hypoxia inducible factor-1 in cancer stem cells (review). Mol Med Rep. 2020;23:1–1.

    Google Scholar 

93. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23:1124–34.

    Google Scholar 

94. Yu R, Hang Y, Tsai HI, Wang D, Zhu H. Iron metabolism: backfire of cancer cell stemness and therapeutic modalities. Cancer Cell Int. 2024;24:157.

    Google Scholar 

95. 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;62:843.

    Google Scholar 

96. Ninomiya T, Ohara T, Noma K, Katsura Y, Katsube R, Kashima H, et al. Iron depletion is a novel therapeutic strategy to target cancer stem cells. Oncotarget. 2017;8:98405–16.

    Google Scholar 

97. Stuelten CH, Mertins SD, Busch JI, Gowens M, Scudiero DA, Burkett MW, et al. Complex display of putative tumor stem cell markers in the NCI60 tumor cell line panel. Stem Cells. 2010;28:649–60.

    Google Scholar 

98. Müller S, Sindikubwabo F, Cañeque T, Lafon A, Versini A, Lombard B, et al. CD44 regulates epigenetic plasticity by mediating iron endocytosis. Nat Chem. 2020;12:929–38.

    Google Scholar 

99. Bourseau-Guilmain E, Griveau A, Benoit JP, Garcion E. The importance of the stem cell marker prominin-1/CD133 in the uptake of transferrin and in iron metabolism in human colon cancer Caco-2 cells. PLoS ONE. 2011;6:e25515.

100. Raggi C, Gammella E, Correnti M, Buratti P, Forti E, Andersen JB, et al. Dysregulation of iron metabolism in cholangiocarcinoma stem-like cells. Sci Rep. 2017;7:17667.

     Google Scholar 

101. Mai TT, Hamaï A, Hienzsch A, Cañeque T, Müller S, Wicinski J, et al. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat Chem. 2017;9:1025–33.

     Google Scholar 

102. Conti L, Lanzardo S, Ruiu R, Cadenazzi M, Cavallo F, Aime S, et al. L-Ferritin targets breast cancer stem cells and delivers therapeutic and imaging agents. Oncotarget. 2016;7:66713–27.

     Google Scholar 

103. Xiao C, Fu X, Wang Y, Liu H, Jiang Y, Zhao Z, et al. Transferrin receptor regulates malignancies and the stemness of hepatocellular carcinoma-derived cancer stem-like cells by affecting iron accumulation. PLoS ONE. 2020;15:e0243812.

104. Baksh SC, Finley LWS. Metabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases. Trends Cell Biol. 2021;31:24–36.

     Google Scholar 

105. 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;122:1580–9.

     Google Scholar 

106. Ambrosini G, Cordani M, Zarrabi A, Alcon-Rodriguez S, Sainz RM, Velasco G, et al. Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies. Cell Commun Signal. 2024;22:36.

     Google Scholar 

107. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30.

     Google Scholar 

108. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26:1326–38.

     Google Scholar 

109. Young JI, Züchner S, Wang G. Regulation of the epigenome by vitamin C. Annu Rev Nutr. 2015;35:545–64.

     Google Scholar 

110. Withey K, Brougham MFH, Paciarotti I, McKenzie JM, Wilson DC, Revuelta Iniesta R. Associations of ferritin and folate status with clinical outcomes in childhood cancer patients: a Prospective Cohort study. Pediatr Blood Cancer. 2025;72:e31645.

     Google Scholar 

111. Jaksch-Bogensperger H, Spiegl-Kreinecker S, Arosio P, Eckl P, Golaszewski S, Ebner Y, et al. Ferritin in glioblastoma. Br J Cancer. 2020;122:1441–4.

     Google Scholar 

112. Schwartzbaum JA, Cornwell DG. Oxidant stress and glioblastoma multiforme risk: serum antioxidants, γ-glutamyl transpeptidase, and ferritin. Nutr Cancer. 2000;38:40–9.

     Google Scholar 

113. Fisher J, Devraj K, Ingram J, Slagle-Webb B, Madhankumar AB, Liu X, et al. Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol-Cell Physiol. 2007;293:C641–9.

     Google Scholar 

114. Wu T, Li Y, Liu B, Zhang S, Wu L, Zhu X, et al. Expression of ferritin light chain (FTL) is elevated in glioblastoma, and FTL silencing inhibits glioblastoma cell proliferation via the GADD45/JNK pathway. PLoS ONE. 2016;11:e0149361.

115. Yang FC, Wang C, Zhu J, Gai QJ, Mao M, He J, et al. Inhibitory effects of temozolomide on glioma cells is sensitized by RSL3-induced ferroptosis but negatively correlated with expression of ferritin heavy chain 1 and ferritin light chain. Lab Investig. 2022;102:741–52.

     Google Scholar 

116. Rosager AM, Sørensen MD, Dahlrot RH, Hansen S, Schonberg DL, Rich JN, et al. Transferrin receptor-1 and ferritin heavy and light chains in astrocytic brain tumors: expression and prognostic value. PLoS ONE. 2017;12:e0182954.

117. Chekhun VF, Lukianova NY, Chekhun SV, Bezdieniezhnykh NO, Zadvorniy TV, Borikun TV, et al. Association of CD44+CD24−/low with markers of aggressiveness and plasticity of cell lines and tumors of patients with breast cancer. Exp Oncol. 2017;39:203–11.

     Google Scholar 

118. Kanojia D, Zhou W, Zhang J, Jie C, Lo P, Wang Q, et al. Proteomic profiling of cancer stem cells derived from primary tumors of HER2/Neu transgenic mice. Proteomics. 2012;12:3407–15.

     Google Scholar 

119. Gong AH, Wei P, Zhang S, Yao J, Yuan Y, Zhou AD, et al. FoxM1 drives a feed-forward STAT3-activation signaling loop that promotes the self-renewal and tumorigenicity of glioblastoma stem-like cells. Cancer Res. 2015;75:2337–48.

     Google Scholar 

120. Ravi V, Madhankumar AB, Abraham T, Slagle-Webb B, Connor JR. Liposomal delivery of ferritin heavy chain 1 (FTH1) siRNA in patient xenograft derived glioblastoma initiating cells suggests different sensitivities to radiation and distinct survival mechanisms. PLoS ONE. 2019;14:e0221952.

121. Lobello N, Biamonte F, Pisanu ME, Faniello MC, Jakopin Ž, Chiarella E, et al. Ferritin heavy chain is a negative regulator of ovarian cancer stem cell expansion and epithelial to mesenchymal transition. Oncotarget. 2016;7:62019–33.

     Google Scholar 

122. Aversa I, Zolea F, Ieranò C, Bulotta S, Trotta AM, Faniello MC, et al. Epithelial-to-mesenchymal transition in FHC-silenced cells: the role of CXCR4/CXCL12 axis. J Exp Clin Cancer Res. 2017;36:104.

     Google Scholar 

123. Lei ZN, Teng QX, Koya J, Liu Y, Chen Z, Zeng L, et al. The correlation between cancer stem cells and epithelial-mesenchymal transition: molecular mechanisms and significance in cancer theragnosis. Front Immunol. 2024;15:1417201.

     Google Scholar 

124. Zhang KH, Tian HY, Gao X, Lei WW, Hu Y, Wang DM, et al. Ferritin heavy chain-mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial–mesenchymal transition. Cancer Res. 2009;69:5340–8.

     Google Scholar 

125. Sioutas A, Vainikka L, Kentson M, Dam Larsen S, Wennerström U, Jacobson P, et al. Oxidant-induced autophagy and ferritin degradation contribute to epithelial– mesenchymal transition through lysosomal iron. J Inflamm Res. 2017;10:29–39.

     Google Scholar 

126. Shesh B, Slagle-Webb B, Shenoy G, Khristov V, Zacharia BE, Connor JR. Uptake of H-ferritin by glioblastoma stem cells and its impact on their invasion capacity. J Cancer Res Clin Oncol. 2023;149:9691–703.

     Google Scholar 

127. Gerlee P, Nelander S. The impact of phenotypic switching on glioblastoma growth and invasion. PLoS Comput Biol. 2012;8:e1002556.

128. Hatzikirou H, Basanta D, Simon M, Schaller K, Deutsch A. Go or Grow’: the key to the emergence of invasion in tumour progression? Math Med Biol. 2012;29:49–65.

     Google Scholar 

129. Lei G, Zhuang L, Gan B. The roles of ferroptosis in cancer: tumor suppression, tumor microenvironment, and therapeutic interventions. Cancer Cell. 2024;42:513–34.

     Google Scholar 

130. Wang J, Wu N, Peng M, Oyang L, Jiang X, Peng Q, et al. Ferritinophagy: research advance and clinical significance in cancers. Cell Death Discov. 2023;9:463.

     Google Scholar 

131. Fang Y, Chen X, Tan Q, Zhou H, Xu J, Gu Q. Inhibiting ferroptosis through disrupting the NCOA4–FTH1 interaction: a new mechanism of action. ACS Cent Sci. 2021;7:980–9.

     Google Scholar 

132. Zhang Y, Kong Y, Ma Y, Ni S, Wikerholmen T, Xi K, et al. Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines. Oncogene. 2021;40:1425–39.

     Google Scholar 

133. 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.

     Google Scholar 

134. Hayashima K, Kimura I, Katoh H. Role of ferritinophagy in cystine deprivation-induced cell death in glioblastoma cells. Biochem Biophys Res Commun. 2021;539:56–63.

     Google Scholar 

135. Daher B, Vučetić M, Pouysségur J. Cysteine depletion, a key action to challenge cancer cells to ferroptotic cell death. Front Oncol. 2020;10:723.

     Google Scholar 

136. Daher B, Parks SK, Durivault J, Cormerais Y, Baidarjad H, Tambutte E, et al. Genetic ablation of the cystine transporter xCT in PDAC cells inhibits mTORC1, growth, survival, and tumor formation via nutrient and oxidative stresses. Cancer Res. 2019;79:3877–90.

     Google Scholar 

137. Wu W, Xu C, Ling X, Fan C, Buckley BP, Chernov MV, et al. Targeting RING domains of Mdm2–MdmX E3 complex activates apoptotic arm of the p53 pathway in leukemia/lymphoma cells. Cell Death Dis. 2015;6:e2035–e2035.

     Google Scholar 

138. Li J, Lama R, Galster SL, Inigo JR, Wu J, Chandra D, et al. Small-Molecule MMRi62 induces ferroptosis and inhibits metastasis in pancreatic cancer via degradation of ferritin heavy chain and mutant p53. Mol Cancer Ther. 2022;21:535–45.

     Google Scholar 

139. Lama R, Galster SL, Xu C, Davison LW, Chemler SR, Wang X. Dual Targeting of MDM4 and FTH1 by MMRi71 for induced protein degradation and p53-independent apoptosis in leukemia cells. Molecules. 2022;27:7665 Nov 8.

     Google Scholar 

140. Mussa A, Mohd Idris RA, Ahmed N, Ahmad S, Murtadha AH, Tengku Din TADAA, et al. High-dose vitamin C for cancer therapy. Pharmaceuticals. 2022;15:711.

     Google Scholar 

141. Baillie N, Carr AC, Peng S. The use of intravenous vitamin C as a supportive therapy for a patient with glioblastoma multiforme. Antioxidants. 2018;7:115.

     Google Scholar 

142. Wang X, Xu S, Zhang L, Cheng X, Yu H, Bao J, et al. Vitamin C induces ferroptosis in anaplastic thyroid cancer cells by ferritinophagy activation. Biochem Biophys Res Commun. 2021;551:46–53.

     Google Scholar 

143. Chevignard M, Câmara-Costa H, Doz F, Dellatolas G. Core deficits and quality of survival after childhood medulloblastoma: a review. Neuro-Oncol Pract. 2017;4:82–97.

     Google Scholar 

144. Baidoo KE, Yong K, Brechbiel MW. Molecular pathways: targeted α-particle radiation therapy. Clin Cancer Res. 2013;19:530–7.

     Google Scholar 

145. Gotorbe C, Segui F, Echavidre W, Durivault J, Blanchard T, Vial V, et al. Exploiting integrin-αVβ3 to enhance radiotherapy efficacy in medulloblastoma via ferroptosis. Curr Oncol. 2024;31:7390–402.

     Google Scholar 

146. Lei G, Zhang Y, Koppula P, Liu X, Zhang J, Lin SH, et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 2020;30:146–62.

     Google Scholar 

147. 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;15:469–84.

     Google Scholar 

148. Olivares-Urbano MA, Griñán-Lisón C, Marchal JA, Núñez MI. CSC radioresistance: a therapeutic challenge to improve radiotherapy effectiveness in cancer. Cells. 2020;9:1651.

     Google Scholar 

149. Caverzan MD, Ibarra LE. Advancing glioblastoma treatment through iron metabolism: a focus on TfR1 and Ferroptosis innovations. Int J Biol Macromol. 2024;278:134777.

     Google Scholar 

150. Loftus LV, Rolle LTA, Wang B, Pienta KJ, Amend SR. Dysregulation of labile iron predisposes chemotherapy resistant cancer cells to ferroptosis. Int J Mol Sci. 2025;26:4193.

     Google Scholar 

151. Liu X, Madhankumar AB, Slagle-Webb B, Sheehan JM, Surguladze N, Connor JR. Heavy chain ferritin siRNA delivered by cationic liposomes increases sensitivity of cancer cells to chemotherapeutic agents. Cancer Res. 2011;71:2240–9.

     Google Scholar 

152. Kazan HH, Urfali-Mamatoglu C, Gunduz U. Iron metabolism and drug resistance in cancer. BioMetals. 2017;30:629–41.

     Google Scholar 

153. Mokarram N, Case A, Hossainy NN, Lyon JG, MacDonald TJ, Bellamkonda R. Device-assisted strategies for drug delivery across the blood-brain barrier to treat glioblastoma. Commun Mater. 2025;6:5.

     Google Scholar 

154. Drechsel DA, Patel M. Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radic Biol Med. 2008;44:1873–86.

     Google Scholar 

155. Levi S, Ripamonti M, Moro AS, Cozzi A. Iron imbalance in neurodegeneration. Mol Psychiatry. 2024;29:1139–52.

     Google Scholar 

156. Cameron E, Campbell A. The orthomolecular treatment of cancer II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact. 1974;9:285–315.

     Google Scholar 

157. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA. 1976;73:3685–9.

     Google Scholar 

158. Chen Y, Li W, Kwon S, Wang Y, Li Z, Hu Q. Small-molecule ferritin degrader as a pyroptosis inducer. J Am Chem Soc. 2023;145:9815–24.

     Google Scholar 

159. Qu C, Dai E, Lai T, Cao G, Liu J, Kang R, et al. Itaconic acid induces ferroptosis by activating ferritinophagy. Biochem Biophys Res Commun. 2021;583:56–62.

     Google Scholar 

160. Sui S, Zhang J, Xu S, Wang Q, Wang P, Pang D. Ferritinophagy is required for the induction of ferroptosis by the bromodomain protein BRD4 inhibitor (+)-JQ1 in cancer cells. Cell Death Dis. 2019;10:331.

     Google Scholar 

161. Huang T, Sun Y, Li Y, Wang T, Fu Y, Li C, et al. Growth inhibition of a novel iron chelator, dpdtc, against hepatoma carcinoma cell lines partly attributed to ferritinophagy-mediated lysosomal ROS generation. Oxid Med Cell Longev. 2018;2018:4928703.

     Google Scholar 

162. Xiu Z, Zhu Y, Han J, Li Y, Yang X, Yang G, et al. Caryophyllene oxide induces ferritinophagy by regulating the NCOA4/FTH1/LC3 pathway in hepatocellular carcinoma. Front Pharmacol. 2022;13:930958.

     Google Scholar 

163. Wang Y, Kuang S, Li K, Chen S, Yang M, Deng K, et al. Astragalin promotes HSCs ferroptosis through NCOA4 mediated ferritinophagy to alleviate liver fibrosis in zebrafish and mice. Commun Biol. 2025;8:1081.

     Google Scholar 

164. Du J, Wang T, Li Y, Zhou Y, Wang X, Yu X, et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med. 2019;131:356–69.

     Google Scholar 

165. Badu-Boateng C, Naftalin RJ. Ascorbate and ferritin interactions: Consequences for iron release in vitro and in vivo and implications for inflammation. Free Radic Biol Med. 2019;133:75–87.

     Google Scholar 

166. Zhu L, You Y, Zhu M, Song Y, Zhang J, Hu J, et al. Ferritin-hijacking nanoparticles spatiotemporally directing endogenous ferroptosis for synergistic anticancer therapy. Adv Mater. 2022;34:2207174.

     Google Scholar 

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