Advances on ferroptosis in hematological malignancies

doi:10.3969/j.issn.1674-490X.2025.06.001

Abstract

Abstract: Hematological malignancies are a group of heterogeneous diseases originating from the hematopoietic and lymphatic systems, characterized fundamentally by malignant clonal proliferation and differentiation arrest. Clinically, there are often significant challenges of poor prognosis and high risk of recurrence. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been confirmed to be closely related to the pathogenesis, progression, and therapeutic response of hematological malignancies. This article systematically reviews the molecular mechanisms of ferroptosis. It focuses on the research developments of hematological malignancies represented by leukemia, multiple myeloma, myelodysplastic syndromes, and lymphoma through the regulation of ferroptosis-related genes and pathways in order to provide a theoretical foundation for a deeper understanding of the disease process and the development of targeted treatment strategies.

Key words: ferroptosis, hematological malignancies, pathological mechanism, targeted therapy

CLC Number:

R733

WU Ting,ZHOU Yue. Advances on ferroptosis in hematological malignancies[J]. Journal of Hebei Medical College for Continuing Education, 2025, 42(6): 1-14.

References

[1] ZHANG N, WU J X, WANG Q, et al. Global burden of hematologic malignancies and evolution patterns over the past 30 years[J]. Blood Cancer J, 2023, 13(1): 82. DOI: 10.1038/s41408-023-00853-3.
[2] LICA J J, PRADHAN B, SAFI K, et al. Promising therapeutic strategies for hematologic malignancies: innovations and potential[J]. Molecules, 2024, 29(17): 4280. DOI: 10.3390/molecules29174280.
[3] ZHOU Q, MENG Y, LI D S, et al. Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies[J]. Signal Transduct Target Ther, 2024, 9: 55. DOI: 10.1038/s41392-024-01769-5.
[4] LIU Y, DU Z F, HUANG J B, et al. Ferroptosis in hematological malignant tumors[J]. Front Oncol, 2023, 13: 1127526. DOI: 10.3389/fonc.2023.1127526.
[5] ZHANG J S, LIU Y X, LI Q, et al. Ferroptosis in hematological malignancies and its potential network with abnormal tumor metabolism[J]. Biomed Pharmacother, 2022, 148: 112747. DOI: 10.1016/j.biopha.2022.112747.
[6] NEWTON K, STRASSER A, KAYAGAKI N, et al. Cell death[J]. Cell, 2024, 187(2): 235-256. DOI: 10.1016/j.cell.2023.11.044.
[7] SUN S M, SHEN J, JIANG J W, et al. Targeting ferroptosis opens new avenues for the development of novel therapeutics[J]. Signal Transduct Target Ther, 2023, 8: 372. DOI: 10.1038/s41392-023-01606-1.
[8] MOU Y H, WANG J, WU J C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer[J]. J Hematol Oncol, 2019, 12(1): 34. DOI: 10.1186/s13045-019-0720-y.
[9] STOCKWELL B R. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications[J]. Cell, 2022, 185(14): 2401-2421. DOI: 10.1016/j.cell.2022.06.003.
[10] FRAZER D M, ANDERSON G J. The regulation of iron transport[J]. Biofactors, 2014, 40(2): 206-214. DOI: 10.1002/biof.1148.
[11] TANG D L, CHEN X, KANG R, et al. Ferroptosis: molecular mechanisms and health implications[J]. Cell Res, 2021, 31(2): 107-125. DOI: 10.1038/s41422-020-00441-1.
[12] STOCKWELL B R, JIANG X J. The chemistry and biology of ferroptosis[J]. Cell Chem Biol, 2020, 27(4): 365-375. DOI: 10.1016/j.chembiol.2020.03.013.
[13] LI J, CAO F, YIN H L, et al. Ferroptosis: past, present and future[J]. Cell Death Dis, 2020, 11(2): 88. DOI: 10.1038/s41419-020-2298-2.
[14] CHEN X, KANG R, KROEMER G, et al. Broadening horizons: the role of ferroptosis in cancer[J]. Nat Rev Clin Oncol, 2021, 18(5): 280-296. DOI: 10.1038/s41571-020-00462-0.
[15] LATUNDE-DADA G O. Ferroptosis: role of lipid peroxidation, iron and ferritinophagy[J]. Biochim Biophys Acta Gen Subj, 2017, 1861(8): 1893-1900. DOI: 10.1016/j.bbagen.2017.05.019.
[16] LIU Y Q, GU W. p53 in ferroptosis regulation: the new weapon for the old guardian[J]. Cell Death Differ, 2022, 29(5): 895-910. DOI: 10.1038/s41418-022-00943-y.
[17] JIANG L, KON N, LI T Y, et al. Ferroptosis as a p53-mediated activity during tumour suppression[J]. Nature, 2015, 520(7545): 57-62. DOI: 10.1038/nature14344.
[18] OU Y, WANG S J, LI D W, et al. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses[J]. Proc Natl Acad Sci USA, 2016, 113(44): E6806-E6812. DOI: 10.1073/pnas.1607152113 DOI:10.1073/pnas.1607152113.
[19] HUANG H X, CHEN M, FENG S B, et al. The dual role of VDAC in cancer: molecular mechanisms and advances in targeted therapy[J]. Biomed Pharmacother, 2025, 191: 118530. DOI: 10.1016/j.biopha.2025.118530.
[20] LIPPER C H, STOFLETH J T, BAI F, et al. Redox-dependent gating of VDAC by mitoNEET[J]. Proc Natl Acad Sci USA, 2019, 116(40): 19924-19929. DOI: 10.1073/pnas.1908271116.
[21] ZHAO Y C, LI Y Q, ZHANG R F, et al. The role of erastin in ferroptosis and its prospects in cancer therapy[J]. OncoTargets Ther, 2020, 13: 5429-5441. DOI: 10.2147/OTT.S254995.
[22] WANG X X, LI M, XU X W, et al. BNIP3-mediated mitophagy attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting ferroptosis through P62-KEAP1-NRF2 pathway activation to maintain iron and redox homeostasis[J]. Acta Pharmacol Sin, 2025, 46(1): 33-51. DOI: 10.1038/s41401-024-01365-x.
[23] ZHU F, DAN T Q, HUA S G. KEAP1-NRF2/HO-1 pathway promotes ferroptosis and neuronal injury in schizophrenia[J]. Brain Behav, 2025, 15(3): e70311. DOI: 10.1002/brb3.70311.
[24] CHANG L C, CHIANG S K, CHEN S E, et al. Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis[J]. Cancer Lett, 2018, 416: 124-137. DOI: 10.1016/j.canlet.2017.12.025.
[25] DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072. DOI: 10.1016/j.cell.2012.03.042.
[26] AQUILANO K, BALDELLI S, CIRIOLO M R. Glutathione: new roles in redox signaling for an old antioxidant[J]. Front Pharmacol, 2014, 5: 196. DOI: 10.3389/fphar.2014.00196.
[27] CONRAD M, PRONETH B. Selenium: tracing another essential element of ferroptotic cell death[J]. Cell Chem Biol, 2020, 27(4): 409-419. DOI: 10.1016/j.chembiol.2020.03.012.
[28] YANG W S, SRIRAMARATNAM R, WELSCH M E, et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156(1/2): 317-331. DOI: 10.1016/j.cell.2013.12.010.
[29] BERSUKER K, HENDRICKS J M, LI Z P, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis[J]. Nature, 2019, 575(7784): 688-692. DOI: 10.1038/s41586-019-1705-2.
[30] FUJITA T C, SOUSA-PEREIRA N, AMARANTE M K, et al. Acute lymphoid leukemia etiopathogenesis[J]. Mol Biol Rep, 2021, 48(1): 817-822. DOI: 10.1007/s11033-020-06073-3.
[31] HSU W Y, WANG L T, LIN P C, et al. Deferasirox causes leukaemia cell death through Nrf2-induced ferroptosis[J]. Antioxidants, 2024, 13(4): 424. DOI: 10.3390/antiox13040424.
[32] DOLL S, FREITAS F P, SHAH R, et al. FSP1 is a glutathione-independent ferroptosis suppressor[J]. Nature, 2019, 575(7784): 693-698. DOI: 10.1038/s41586-019-1707-0.
[33] NIU F, YANG R Y, FENG H, et al. A GPX4 non-enzymatic domain and MDM2 targeting peptide PROTAC for acute lymphoid leukemia therapy through ferroptosis induction[J]. Biochem Biophys Res Commun, 2023, 684: 149125. DOI: 10.1016/j.bbrc.2023.149125.
[34] ASHOUB M H, AMIRI M, FATEMI A, et al. Evaluation of ferroptosis-based anti-leukemic activities of ZnO nanoparticles synthesized by a green route against Pre-B acute lymphoblastic leukemia cells(Nalm-6 and REH)[J]. Heliyon, 2024, 10(17): e36608. DOI: 10.1016/j.heliyon.2024.e36608.
[35] WANG Z L, CHEN X W, LIU N, et al. A nuclear long non-coding RNA LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis[J]. Mol Ther, 2021, 29(1): 263-274. DOI: 10.1016/j.ymthe.2020.09.024.
[36] LE Y, ZHU S C, PENG H L, et al. Unveiling the omics tapestry of B-acute lymphoblastic leukemia: bridging genomics, metabolomics, and immunomics[J]. Sci Rep, 2025, 15(1): 3188. DOI: 10.1038/s41598-025-87684-3.
[37] TIAN C, ZHENG M, LAN X, et al. Silencing LCN2 enhances RSL3-induced ferroptosis in T cell acute lymphoblastic leukemia[J]. Gene, 2023, 879: 147597. DOI: 10.1016/j.gene.2023.147597.
[38] TANG X. Prognostic value, biological role, and mechanisms of LCN2 in childhood acute lymphoblastic leukemia[J]. Am J Cancer Res, 2025, 15(4): 1759-1776. DOI: 10.62347/asrb7620.
[39] LENG X, LIN H, DING T, et al. Lipocalin 2 is required for BCR-ABL-induced tumorigenesis[J]. Oncogene, 2008, 27(47): 6110-6119. DOI: 10.1038/onc.2008.209.
[40] AKIYAMA H, ZHAO R, OSTERMANN L B, et al. Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia[J]. Leukemia, 2024, 38(4): 729-740. DOI: 10.1038/s41375-023-02117-2.
[41] WEBER S, PARMON A, KURRLE N, et al. The clinical significance of iron overload and iron metabolism in myelodysplastic syndrome and acute myeloid leukemia[J]. Front Immunol, 2021, 11: 627662. DOI: 10.3389/fimmu.2020.627662.
[42] DU J, WANG T T, LI Y C, et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin[J]. Free Radic Biol Med, 2019, 131: 356-369. DOI: 10.1016/j.freeradbiomed.2018.12.011.
[43] WANG D, WANG F L, ZHANG H X, et al. Circadian clock protein Bmal1 accelerates acute myeloid leukemia by inhibiting ferroptosis through the EBF3/ALOX15 axis[J]. Cancer Sci, 2023, 114(8): 3446-3460. DOI: 10.1111/cas.15875.
[44] ZHENG H, WU T, LIN Z, et al. Targeting BMAL1 reverses drug resistance of acute myeloid leukemia cells and promotes ferroptosis through HMGB1-GPX4 signaling pathway[J]. J Cancer Res Clin Oncol, 2024, 150(5): 231. DOI: 10.1007/s00432-024-05753-y.
[45] KONG Q, LIANG Q X, TAN Y L, et al. Induction of ferroptosis by SIRT1 knockdown alleviates cytarabine resistance in acute myeloid leukemia by activating the HMGB1/ACSL4 pathway[J]. Int J Oncol, 2024, 66: 2. DOI: 10.3892/ijo.2024.5708.
[46] ASHOUB M H, RAZAVI R, HEYDARYAN K, et al. Targeting ferroptosis for leukemia therapy: exploring novel strategies from its mechanisms and role in leukemia based on nanotechnology[J]. Eur J Med Res, 2024, 29(1): 224. DOI: 10.1186/s40001-024-01822-7.
[47] BIRSEN R, LARRUE C, DECROOCQ J, et al. APR-246 induces early cell death by ferroptosis in acute myeloid leukemia[J]. Haematologica, 2022, 107(2): 403-416. DOI: 10.3324/haematol.2020.259531.
[48] PENG X, ZHANG M Q Z, CONSERVA F, et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase[J]. Cell Death Dis, 2013, 4(10): e881. DOI: 10.1038/cddis.2013.417.
[49] ALI D, JÖNSSON-VIDESÄTER K, DENEBERG S, et al. APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells[J]. Eur J Haematol, 2011, 86(3): 206-215. DOI: 10.1111/j.1600-0609.2010.01557.x.
[50] ZHONG S J, LIU X L, KANEKO T, et al. Peptide blockers of PD-1-PD-L1 interaction reinvigorate PD-1-suppressed T cells and curb tumor growth in mice[J]. Cells, 2024, 13(14): 1193. DOI: 10.3390/cells13141193.
[51] ZAROBKIEWICZ M K, BOJARSKA-JUNAK A A. The mysterious actor-γδ T lymphocytes in chronic lymphocytic leukaemia(CLL)[J]. Cells, 2022, 11(4): 661. DOI: 10.3390/cells11040661.
[52] EIKEN A P, SCHMITZ E, DRENGLER E M, et al. The novel anti-cancer agent, SpiD3, is cytotoxic in CLL cells resistant to ibrutinib or venetoclax[J]. Hemato, 2024, 5(3): 321-339. DOI: 10.3390/hemato5030024.
[53] NARDI F, DEL PRETE R, DRAGO R, et al. Apoliprotein E-mediated ferroptosis controls cellular proliferation in chronic lymphocytic leukemia[J]. Leukemia, 2025, 39(1): 122-133. DOI: 10.1038/s41375-024-02442-0.
[54] GONG H, LI H, YANG Q, et al. A ferroptosis molecular subtype-related signature for predicting prognosis and response to chemotherapy in patients with chronic lymphocytic leukemia[J]. Bio Med Res Int, 2022, 2022(1): 5646275. DOI: 10.1155/2022/5646275.
[55] PAN B H, LI Y, XU Z D, et al. Identifying a novel ferroptosis-related prognostic score for predicting prognosis in chronic lymphocytic leukemia[J]. Front Immunol, 2022, 13: 962000. DOI: 10.3389/fimmu.2022.962000.
[56] ZHAO Y, HUANG Z N, PENG H L. Molecular mechanisms of ferroptosis and its roles in hematologic malignancies[J]. Front Oncol, 2021, 11: 743006. DOI: 10.3389/fonc.2021.743006.
[57] SCHMITZ E, RIDOUT A, SMITH A L, et al. Immunogenic cell death traits emitted from chronic lymphocytic leukemia cells following treatment with a novel anti-cancer agent, SpiD3[J]. Biomedicines, 2024, 12(12): 2857. DOI: 10.3390/biomedicines12122857.
[58] WANG W M, GREEN M, CHOI J E, et al. CD8⁺ T cells regulate tumour ferroptosis during cancer immunotherapy[J]. Nature, 2019, 569(7755): 270-274. DOI: 10.1038/s41586-019-1170-y.
[59] LIU X, ROTHE K, YEN R, et al. A novel AHI-1-BCR-ABL-DNM2 complex regulates leukemic properties of primitive CML cells through enhanced cellular endocytosis and ROS-mediated autophagy[J]. Leukemia, 2017, 31(11): 2376-2387. DOI: 10.1038/leu.2017.108.
[60] ZENG C W, NIE D R, WANG X F, et al. Combined targeting of GPX4 and BCR-ABL tyrosine kinase selectively compromises BCR-ABL+leukemia stem cells[J]. Mol Cancer, 2024, 23(1): 240. DOI: 10.1186/s12943-024-02162-0.
[61] LIU S H, WU W, CHEN Q Q, et al. TXNRD1: a key regulator involved in the ferroptosis of CML cells induced by cysteine depletion in vitro[J]. Oxid Med Cell Longev, 2021, 2021: 7674565. DOI: 10.1155/2021/7674565.
[62] ZHU M, ZHAO Y Q, XU L, et al. Mn-Zn ferrite nanoparticles inducing ferroptosis to reverse the resistance in CML cells[J]. J Transl Med, 2025, 23(1): 1071. DOI: 10.1186/s12967-025-07107-9.
[63] CUI Y Q, LI Y T, JI J M, et al. Dynamic Single-Cell RNA-Seq reveals mechanism of Selinexor-Resistance in chronic myeloid leukemia[J]. Int Immunopharmacol, 2024, 134: 112212. DOI: 10.1016/j.intimp.2024.112212.
[64] KAZANDJIAN D. Multiple myeloma epidemiology and survival: a unique malignancy[J]. Semin Oncol, 2016, 43(6): 676-681. DOI: 10.1053/j.seminoncol.2016.11.004.
[65] CHEN C, HE L, WANG X, et al. Leonurine promotes the maturation of healthy donors and multiple myeloma patients derived-dendritic cells via the regulation on arachidonic acid metabolism[J]. Front Pharmacol, 2023, 14: 1104403. DOI: 10.3389/fphar.2023.1104403.
[66] PANARONI C, FULZELE K, MORI T, et al. Multiple myeloma cells induce lipolysis in adipocytes and uptake fatty acids through fatty acid transporter proteins[J]. Blood, 2022, 139(6): 876-888. DOI: 10.1182/blood.2021013832.
[67] JIANG H M, WANG L J, ZHANG Q G, et al. Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma[J]. Oncogene, 2024, 43(21): 1644-1653. DOI: 10.1038/s41388-024-03020-5.
[68] LIU X, XU P P, WANG L L, et al. Cholesterol levels provide prognostic information in patients with multiple myeloma[J]. Clin Lab, 2020, 66(4). DOI: 10.7754/Clin.Lab.2019.190824.
[69] XIAN M, WANG Q, XIAO L L, et al. Leukocyte immunoglobulin-like receptor B1(LILRB1)protects human multiple myeloma cells from ferroptosis by maintaining cholesterol homeostasis[J]. Nat Commun, 2024, 15: 5767. DOI: 10.1038/s41467-024-50073-x.
[70] BORDINI J, MORISI F, CERRUTI F, et al. Iron causes lipid oxidation and inhibits proteasome function in multiple myeloma cells: a proof of concept for novel combination therapies[J]. Cancers, 2020, 12(4): 970. DOI: 10.3390/cancers12040970.
[71] ZHANG Y Y, HE F, HU W, et al. Bortezomib elevates intracellular free Fe(2+)by enhancing NCOA4-mediated ferritinophagy and synergizes with RSL-3 to inhibit multiple myeloma cells[J]. Ann Hematol, 2024, 103(9): 3627-3637. DOI: 10.1007/s00277-024-05762-4.
[72] ZHANG J S, LIU Y X, LI Q, et al. ACSL4: a double-edged sword target in multiple myeloma, promotes cell proliferation and sensitizes cell to ferroptosis[J]. Carcinogenesis, 2023, 44(3): 242-251. DOI: 10.1093/carcin/bgad015.
[73] PETZER V, THEURL I, WEISS G, et al. EnvIRONmental aspects in myelodysplastic syndrome[J]. Int J Mol Sci, 2021, 22(10): 5202. DOI: 10.3390/ijms22105202.
[74] YANG Y F, HAN J P, WEI Y X, et al. Research progress on ferroptosis in Myelodysplastic syndromes[J]. Front Pharmacol, 2025, 16: 1561072. DOI: 10.3389/fphar.2025.1561072.
[75] YANG L Y, ZHANG M Y, LIU M Y, et al. Loss of FTH1 induces ferritinophagy-mediated ferroptosis in anaemia of myelodysplastic syndromes[J]. J Cell Mol Med, 2025, 29(1): e70350. DOI:10.1111/jcmm.70350.
[76] LIU W, WU M, HUANG Z, et al. C-myb hyperactivity leads to myeloid and lymphoid malignancies in zebrafish[J]. Leukemia, 2017, 31(1): 222-233. DOI: 10.1038/leu.2016.170.
[77] LIU L, YANG C Y, ZHU L, et al. RSL3 enhances ROS-mediated cell apoptosis of myelodysplastic syndrome cells through MYB/Bcl-2 signaling pathway[J]. Cell Death Dis, 2024, 15(7): 465. DOI: 10.1038/s41419-024-06866-5.
[78] MAGINA K N, PREGARTNER G, ZEBISCH A, et al. Cytarabine dose in the consolidation treatment of AML: a systematic review and meta-analysis[J]. Blood, 2017, 130(7): 946-948. DOI: 10.1182/blood-2017-04-777722.
[79] LV Q, NIU H Y, YUE L Z, et al. Abnormal ferroptosis in myelodysplastic syndrome[J]. Front Oncol, 2020, 10: 1656. DOI: 10.3389/fonc.2020.01656.
[80] TAKAHARA T, NAKAMURA S, TSUZUKI T, et al. The immunology of DLBCL[J]. Cancers, 2023, 15(3): 835. DOI: 10.3390/cancers15030835.
[81] BIAN W X, LI H R, CHEN Y H, et al. Ferroptosis mechanisms and its novel potential therapeutic targets for DLBCL[J]. Biomed Pharmacother, 2024, 173: 116386. DOI: 10.1016/j.biopha.2024.116386.
[82] KOTKARANTA P, CHAN M, VUOLIO T, et al. DLBCL cells with ferroptosis morphology can be detected with a deep convolutional neural network[J]. Biomed Pharmacother, 2025, 182: 117785. DOI: 10.1016/j.biopha.2024.117785.
[83] MASNIKOSA R, CVETKOVIC' Z, PIRIC' D. Tumor biology hides novel therapeutic approaches to diffuse large B-cell lymphoma: a narrative review[J]. Int J Mol Sci, 2024, 25(21): 11384. DOI: 10.3390/ijms252111384.
[84] SCHMITT A, XU W D, BUCHER P, et al. Research progress on ferroptosis in Myelodysplastic syndromes[J]. Blood, 2021, 138(10): 871-884. DOI: 10.1182/blood.2020009404.
[85] ZHANG S X, WANG J, HUANG G X, et al. TCP1 expression alters the ferroptosis sensitivity of diffuse large B-cell lymphoma subtypes by stabilising ACSL4 and influences patient prognosis[J]. Cell Death Dis, 2024, 15: 611. DOI: 10.1038/s41419-024-07001-0.
[86] XIONG D, GENG C J, ZENG L Y, et al. Artesunate induces ferroptosis by regulating MT1G and has an additive effect with doxorubicin in diffuse large B-cell lymphoma cells[J]. Heliyon, 2024, 10(7): e28584. DOI: 10.1016/j.heliyon.2024.e28584.
[87] ZHANG Y, TAN H, DANIELS J D, et al. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model[J]. Cell Chem Biol, 2019, 26(5): 623-633. DOI: 10.1016/j.chembiol.2019.01.008.
[88] KINOWAKI Y, KURATA M, ISHIBASHI S, et al. Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma[J]. Lab Invest, 2018, 98(5): 609-619. DOI: 10.1038/s41374-017-0008-1.