Ferroptosis shows promise as a cancer treatment due to lipid hydroperoxide accumulation in an iron-dependent manner. Isocitrate dehydrogenase 1 (IDH1) mutation is common in gliomas and D-2-hydroxyglutarate (D-2HG) sensitizes cancer cells to ferroptosis. However, the regulation of ferroptosis in IDH1 mutant gliomas remains unclear. We hypothesize that IDH1 mutations induce glioma ferroptosis by regulating iron metabolism and antioxidant systems through the heme-BACH axis.
Results:
IDH1 mutation induces ferroptosis in astrocytes and glioma cells demonstrated by growth inhibition, mitochondrial damage, and lipid peroxidation. In IDH1-mutant gliomas, both Fe2+ and reactive oxygen species accumulate due to impaired heme biosynthesis and thus BACH activation-dependent transcriptional repression of iron homeostasis and antioxidant response-related genes. The heme analogs zinc and tin protoporphyrin IX (ZnPP and SnPP) function as competitive inhibitors to reduce heme-dependent degradation of BACH and to exacerbate ferroptosis, especially for IDH1 mutants at extremely low concentrations. Primary mouse astrocytes and human glioma cell lines were used to determine the effect of IDH1 mutation on ferroptosis, while orthotopic xenograft models were used to evaluate heme analog efficacy. The drug affinity responsive target stability assay was used to determine the interaction between heme and its analog and BACH.
Innovation and Conclusions:
We discover that IDH1 mutation induces ferroptosis by activating the heme-BACH axis. ZnPP, previously believed to function exclusively as a heme oxygenase-1 inhibitor, can competitively bind to BACH to exacerbate ferroptosis and potently suppress IDH1-mutant gliomas. This study reveals a novel metabolic mechanism for inducing ferroptosis and provides a potential therapeutic target for IDH-mutant gliomas. Paraffin-embedded human glioma samples were collected from Xijing Hospital, the First Affiliated Hospital of the Fourth Military Medical University (China) (project number: KY20233192-1). Antioxid. Redox Signal. 44, 145–163.
AntonelliM, PolianiPL. Adult type diffuse gliomas in the new 2021 WHO Classification. Pathologica, 2022; 114(6):397–409; doi: 10.32074/1591-951X-823
2.
BurchJS, MarceroJR, MaschekJA, et al.Glutamine via α-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis. Blood, 2018; 132(10):987–998; doi: 10.1182/blood-2018-01-829036
3.
CairnsRA, MakTW. Oncogenic isocitrate dehydrogenase mutations: Mechanisms, models, and clinical opportunities. Cancer Discov, 2013; 3(7):730–741; doi: 10.1158/2159-8290.CD-13-0083
4.
CanovaiE, FarréR, De HertoghG, et al.Tranilast reduces intestinal ischemia reperfusion injury in rats through the upregulation of Heme-Oxygenase (HO)-1. J Clin Med, 2025; 14(9):3254; doi: 10.3390/jcm14093254
5.
ChenY, GuoX, ZengY, et al.Ferroptosis contributes to catecholamine-induced cardiotoxicity and pathological remodeling. Free Radic Biol Med, 2023; 207:227–238; doi: 10.1016/j.freeradbiomed.2023.07.025
6.
CuiD, RenJ, ShiJ, et al.R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt/beta-catenin signaling. Int J Biochem Cell Biol, 2016; 73:72–81; doi: 10.1016/j.biocel.2016.02.007
7.
DavudianS, MansooriB, ShajariN, et al.BACH1, the master regulator gene: A novel candidate target for cancer therapy. Gene, 2016; 588(1):30–37; doi: 10.1016/j.gene.2016.04.040
8.
DrummondGS, KappasA. Sn-Protoporphyrin inhibition of fetal and neonatal brain heme oxygenase. Transplacental passage of the metalloporphyrin and prenatal suppression of hyperbilirubinemia in the newborn animal. J Clin Invest, 1986; 77(3):971–976; doi: 10.1172/JCI112398
9.
DunwoodieSL. The role of hypoxia in development of the Mammalian embryo. Dev Cell, 2009; 17(6):755–773; doi: 10.1016/j.devcel.2009.11.008
10.
FangX, HuangZ, ZhaiK, et al.Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice. Sci Transl Med, 2021; 13(600):eabc7275; doi: 10.1126/scitranslmed.abc7275
11.
GuY, YangR, YangY, et al.IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis. Blood, 2021; 137(7):945–958; doi: 10.1182/blood.2020007075
12.
IgarashiK, Watanabe-MatsuiM. Wearing red for signaling: The heme-bach axis in heme metabolism, oxidative stress response and iron immunology. Tohoku J Exp Med, 2014; 232(4):229–253; doi: 10.1620/tjem.232.229
13.
JiangX, StockwellBR, ConradM. Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol, 2021; 22(4):266–282; doi: 10.1038/s41580-020-00324-8
14.
KimNI, NohMG, KimJH, et al.Frequency and prognostic value of IDH mutations in Korean patients with cholangiocarcinoma. Front Oncol, 2020; 10:1514; doi: 10.3389/fonc.2020.01514
15.
KobayashiM, KatoH, HadaH, et al.Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency. Haematologica, 2017; 102(3):454–465; doi: 10.3324/haematol.2016.151043
16.
KorlaPK, ChenCC, GracillaDE, et al.Somatic mutational landscapes of adherens junctions and their functional consequences in cutaneous melanoma development. Theranostics, 2020; 10(26):12026–12043; doi: 10.7150/thno.46705
LeiG, ZhuangL, GanB. Targeting Ferroptosis as a vulnerability in cancer. Nat Rev Cancer, 2022; 22(7):381–396; doi: 10.1038/s41568-022-00459-0
19.
LiJ, LiuJ, ZhouZ, et al.Tumor-specific GPX4 degradation enhances Ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer. Sci Transl Med, 2023; 15(720):eadg3049; doi: 10.1126/scitranslmed.adg3049
20.
LiYY, LiuCY, LiuM, et al.Protective effects of HO-1 pathway on lung injury subsequent to limb ischemia reperfusion. Kaohsiung J Med Sci, 2019; 35(7):417–424; doi: 10.1002/kjm2.12070
21.
LignittoL, LeBoeufSE, HomerH, et al.Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of Bach1. Cell, 2019; 178(2):316–329.e18; doi: 10.1016/j.cell.2019.06.003
22.
LiuL, HeJ, SunG, et al.The N6-methyladenosine modification enhances Ferroptosis resistance through inhibiting SLC7A11 mRNA Deadenylation in Hepatoblastoma. Clin Transl Med, 2022; 12(5):e778; doi: 10.1002/ctm2.778
23.
LomenickB, JungG, WohlschlegelJA, et al.Target identification using Drug Affinity Responsive Target Stability (DARTS). Curr Protoc Chem Biol, 2011; 3(4):163–180; doi: 10.1002/9780470559277.ch110180
24.
LouisDN, PerryA, WesselingP, et al.The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol, 2021; 23(8):1231–1251; doi: 10.1093/neuonc/noab106
25.
MellinghoffIK, Penas-PradoM, PetersKB, et al.Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; results of a first-in-human phase I trial. Clin Cancer Res, 2021; 27(16):4491–4499; doi: 10.1158/1078-0432.CCR-21-0611
26.
NatsumeA, ArakawaY, NaritaY, et al.The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas. Neuro Oncol, 2023; 25(2):326–336; doi: 10.1093/neuonc/noac155
27.
NishizawaH, MatsumotoM, ShindoT, et al.Ferroptosis is controlled by the coordinated transcriptional regulation of glutathione and labile iron metabolism by the transcription factor BACH1. J Biol Chem, 2020; 295(1):69–82; doi: 10.1074/jbc.RA119.009548
28.
PirozziCJ, CarpenterAB, WaitkusMS, et al.Mutant IDH1 disrupts the mouse Subventricular zone and alters brain tumor progression. Mol Cancer Res, 2017; 15(5):507–520; doi: 10.1158/1541-7786.MCR-16-0485
29.
PirozziCJ, YanH. The implications of IDH mutations for cancer development and therapy. Nat Rev Clin Oncol, 2021; 18(10):645–661; doi: 10.1038/s41571-021-00521-0
30.
RegehlyM, GreishK, RancanF, et al.Water-soluble polymer conjugates of ZnPP for photodynamic tumor therapy. Bioconjug Chem, 2007; 18(2):494–499; doi: 10.1021/bc060216p
31.
RochetteL, ZellerM, CottinY, et al.Redox functions of heme oxygenase-1 and Biliverdin reductase in diabetes. Trends Endocrinol Metab, 2018; 29(2):74–85; doi: 10.1016/j.tem.2017.11.005
32.
Ruelas CastilloJ, NeupaneP, KaranikaS, et al.The heme oxygenase-1 Metalloporphyrin inhibitor Stannsoporfin enhances the bactericidal activity of a novel regimen for multidrug-resistant tuberculosis in a murine model. Antimicrob Agents Chemother, 2024; 68(2):e0104323; doi: 10.1128/aac.01043-23
33.
SasakiM, KnobbeCB, ItsumiM, et al.D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev, 2012; 26(18):2038–2049; doi: 10.1101/gad.198200.112
34.
ShirahataM, OnoT, StichelD, et al.Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol, 2018; 136(1):153–166; doi: 10.1007/s00401-018-1849-4
SuR, DongL, LiC, et al.R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell, 2018; 172(1–2):90–105.e23; doi: 10.1016/j.cell.2017.11.031
37.
SubramanianA, TamayoP, MoothaVK, et al.Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A, 2005; 102(43):15545–15550; doi: 10.1073/pnas.0506580102
38.
SunJ, BrandM, ZenkeY, et al.Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network. Proc Natl Acad Sci U S A, 2004; 101(6):1461–1466; doi: 10.1073/pnas.0308083100
39.
SunL, WangH, YuS, et al.Herceptin induces Ferroptosis and mitochondrial dysfunction in H9c2 cells. Int J Mol Med, 2022; 49(2):17; doi: 10.3892/ijmm.2021.5072
40.
TangB, ZhuJ, WangY, et al.Targeted xCT-mediated Ferroptosis and protumoral polarization of macrophages is effective against HCC and enhances the efficacy of the anti-PD-1/L1 response. Adv Sci (Weinh), 2023; 10(2):e2203973; doi: 10.1002/advs.202203973
41.
TsaiLT, WuCT, LiuCY, et al.Zinc protoporphyrin accumulation as a positive regulator of renal heme oxygenase-1 participates in the progression of chronic kidney disease. Biochem Biophys Res Commun, 2025; 770:152014; doi: 10.1016/j.bbrc.2025.152014
42.
TurkalpZ, KaramchandaniJ, DasS. IDH mutation in glioma: New insights and promises for the future. JAMA Neurol, 2014; 71(10):1319–1325; doi: 10.1001/jamaneurol.2014.1205
43.
TynerJW, TognonCE, BottomlyD, et al.Functional genomic landscape of acute myeloid Leukaemia. Nature, 2018; 562(7728):526–531; doi: 10.1038/s41586-018-0623-z
44.
UrsiniF, MaiorinoM. Lipid peroxidation and Ferroptosis: The role of GSH and GPx4. Free Radic Biol Med, 2020; 152:175–185; doi: 10.1016/j.freeradbiomed.2020.02.027
45.
WangH, YuX, LiuD, et al.VDR activation attenuates renal tubular epithelial cell Ferroptosis by regulating Nrf2/HO-1 signaling pathway in diabetic nephropathy. Adv Sci (Weinh), 2024; 11(10):e2305563; doi: 10.1002/advs.202305563
46.
WangTX, LiangJY, ZhangC, et al.The Oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to Ferroptosis. Cell Death Dis, 2019; 10(10):755; doi: 10.1038/s41419-019-1984-4
47.
WakamatsuJI. Evidence of the mechanism underlying zinc protoporphyrin IX formation in nitrite/nitrate-free dry-cured Parma ham. Meat Sci, 2022; 192:108905; doi: 10.1016/j.meatsci.2022.108905
48.
Watanabe-MatsuiM, MatsumotoT, MatsuiT, et al.Heme binds to an intrinsically disordered region of Bach2 and alters its conformation. Arch Biochem Biophys, 2015; 565:25–31; doi: 10.1016/j.abb.2014.11.005
49.
WielC, Le GalK, IbrahimMX, et al.BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell, 2019; 178(2):330–345.e22; doi: 10.1016/j.cell.2019.06.005
50.
WuL, LvL, XiangY, et al.Rosmarinic acid protects against acetaminophen-induced hepatotoxicity by suppressing Ferroptosis and oxidative stress through Nrf2/HO-1 activation in mice. Mar Drugs, 2025; 23(7):373; doi: 10.3390/md23070287
51.
YaoL, HaoY, WenG, et al.Induction of heme oxygenase-1 modifies the systemic immunity and reduces atherosclerotic lesion development in ApoE deficient mice. Front Pharmacol, 2022; 13:809469; doi: 10.3389/fphar.2022.809469
52.
YuD, LiuY, ZhouY, et al.Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism. Proc Natl Acad Sci U S A, 2020; 117(18):9964–9972; doi: 10.1073/pnas.1913633117
53.
YuY, YanY, NiuF, et al.Ferroptosis: A cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov, 2021; 7(1):193; doi: 10.1038/s41420-021-00579-w
YuanY, ZhaiY, ChenJ, et al.Kaempferol ameliorates oxygen-glucose deprivation/reoxygenation-induced neuronal Ferroptosis by activating Nrf2/SLC7A11/GPX4 axis. Biomolecules, 2021; 11(7):923; doi: 10.3390/biom11070923
56.
Zenke-KawasakiY, DohiY, KatohY, et al.Heme induces ubiquitination and degradation of the transcription factor Bach1. Mol Cell Biol, 2007; 27(19):6962–6971; doi: 10.1128/MCB.02415-06
57.
ZhangJ, ChambersI, YunS, et al.Hrg1 promotes heme-iron recycling during hemolysis in the zebrafish kidney. PLoS Genet, 2018; 14(9):e1007665; doi: 10.1371/journal.pgen.1007665
58.
ZhengC, ZhangB, LiY, et al.Donafenib and GSK-J4 synergistically induce Ferroptosis in liver cancer by upregulating HMOX1 expression. Adv Sci (Weinh), 2023; 10(22):e2206798; doi: 10.1002/advs.202206798
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
