Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press86510.17650/2313-805X-2026-13-2-8-18REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИReview ArticleFerroptosis of hematopoietic stem cells in the pathogenesis of age-associated solid tumorsФерроптоз гемопоэтических стволовых клеток в патогенезе возраст-ассоциированных солидных опухолейhttps://orcid.org/0000-0002-0401-9900ShevchenkoValery E.ШевченкоВалерий Евгеньевич
Russian Federation
vshev2015@yandex.ruhttps://orcid.org/0000-0001-9626-6847KushnirT. I.КушнирТ. И.
Russian Federation
vshev2015@yandex.ruhttps://orcid.org/0000-0003-2694-5232GudkovaM. V.ГудковаМ. В.
Russian Federation
vshev2015@yandex.ruhttps://orcid.org/0000-0002-0154-8604ArnotskayaN. E.АрноцкаяН. Е.
Russian Federation
vshev2015@yandex.ruN. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России190620261328181905202621052026Copyright ©; 2026, ABV-PressCopyright ©; 2026, АБВ-пресс2026ABV-PressАБВ-прессhttps://creativecommons.org/licenses/by/4.0/https://umo.abvpress.ru/jour/article/view/865

Ferroptosis (FP), an iron-dependent form of regulated cell death driven by the accumulation of lipid peroxides and the impairment of antioxidant defenses, has recently emerged as a key pathophysiological mechanism in oncogenesis and aging. Concurrently, growing evidence indicates that age-associated alterations in hematopoietic stem cells, including the development of clonal hematopoiesis of indeterminate potential (CHIP), exert systemic effects on the formation of a pro-oncogenic microenvironment outside the bone marrow. This review evaluates the hypothesis that FP acts as a key selective mechanism (in aging hematopoiesis, driving the depletion of the normal hematopoietic stem cells pool while promoting the corresponding expansion of mutant clones with relative resistance to oxidative and iron-dependent stress.

We examine in detail the molecular mechanisms of FP (the SLC7A11–GSH–GPX4 axis, iron metabolism, lipid peroxidation, and the role of mitochondria), involutive shifts in the metabolic and redox status of hematopoietic stem cells, and their links to myeloid-biased differentiation and the inflammatory phenotype of CHIP clones. Special attention is dedicated to how macrophages and monocytes derived from FP-resistant clones sustain chronic, low-grade inflammation (inflammaging), impair antitumor immune surveillance, and shape a tissue stroma conducive to the initiation and progression of age-associated solid tumors. Based on clinical and experimental data, we discuss the pathogenetic link between CHIP and an elevated risk of lung, liver, pancreatic, and colorectal cancers. Furthermore, the role of disrupted iron homeostasis and lipid metabolism directly within the tumor microenvironment is analyzed. We propose the concept of FP as a “selection filter” in aging hematopoiesis that dictates the clonal selection of cells with pro-oncogenic properties. In conclusion, we evaluate the prospects of targeted modulation of FP and pro-inflammatory signaling pathways in distinct cell types as a novel strategy for the prevention and treatment of age-associated solid tumors.

Ферроптоз (ФП) – железозависимая форма регулируемой клеточной гибели, обусловленная накоплением перекисей липидов и нарушением антиоксидантной защиты, – в последние годы рассматривается как ключевой патофизиологический механизм в онкогенезе и старении. Одновременно с этим накапливаются данные о том, что возрастные изменения гемопоэтических стволовых клеток, включая развитие клонального гемопоэза неопределенного потенциала (CHIP), оказывают системное влияние на формирование проонкогенного микроокружения вне костного мозга. В настоящем обзоре обосновывается гипотеза, согласно которой ФП является ключевым селективным механизмом в стареющем гемопоэзе, способствующим истощению пула нормальных гемопоэтических стволовых клеток и сопряженному расширению мутантных клонов, обладающих относительной устойчивостью к окислительному и железозависимому стрессам.

В работе подробно рассматриваются молекулярные механизмы ФП (ось SLC7A11–GSH–GPX4, метаболизм железа, липидная пероксидация, роль митохондрий), инволютивные изменения метаболического и окислительно-восстановительного статусов гемопоэтических стволовых клеток, а также их связь с миелоидным сдвигом дифференцировки и воспалительным фенотипом CHIP-клонов. Особое внимание уделено тому, как макрофаги и моноциты, происходящие из устойчивых к ФП клонов, поддерживают хроническое низкоинтенсивное воспаление (инфламейджинг), нарушают противоопухолевый иммунный надзор и формируют тканевую строму, благоприятную для инициации и прогрессии возраст-ассоциированных солидных опухолей. На основе клинических и экспериментальных данных рассматривается патогенетическая связь CHIP с высоким риском развития рака легкого, печени, поджелудочной железы и колоректального рака. Проанализирована роль нарушенного гомеостаза железа и липидного обмена непосредственно в опухолевом микроокружении. Предлагается концепция ФП как «отборочного фильтра» в стареющем гемопоэзе, определяющего селекцию клонов с проонкогенными свойствами. Также рассматриваются возможности избирательного воздействия на ФП и провоспалительные сигнальные пути в различных типах клеток для профилактики и лечения возраст-ассоциированных солидных опухолей.

ferroptosishematopoietic stem cellaging hematopoiesisclonal hematopoiesis of indeterminate potentialage-associated solid tumorферроптозгемопоэтическая стволовая клеткастарение гемопоэзаклональный гемопоэз неопределенного потенциалавозраст-ассоциированная солидная опухольThe work was carried out within the framework of the budget project on the topic “Development of a test system for the assessment and subsequent correction of the ferroptosis status in hematopoietic stem cells of the aging human body” (No. 125070707993-0).Работа выполнена в рамках бюджетного проекта по теме «Разработка тест-системы для оценки и последующей коррекции статуса ферроптоза в гемопоэтических стволовых клетках стареющего организма человека» (№ 125070707993-0).Rossi D.J., Jamieson C.H., Weissman I.L. Stems cells and the pathways to aging and cancer. Cell 2008;132(6):681–96. DOI: 10.1016/j.cell.2008.01.038Beerman I., Rossi D.J. Epigenetic control of stem cell potential during homeostasis, aging, and disease. Cell Stem Cell 2015;16(6):613–25. DOI: 10.1016/j.stem.2015.05.009López-Otín C., Blasco M.A., Partridge L. et al. The hallmarks of aging. Cell 2013;153(6):1194–217. DOI: 10.1016/j.cell.2013.05.039Geiger H., de Haan G., Florian M.C. The ageing haematopoietic stem cell compartment. Nat Rev Immunol 2013;13(5):376–89. DOI: 10.1038/nri3433Shevchenko V.E., Kushnir T.I., Gudkova M.V., Arnotskaya N.E. Ferroptosis determinants – potential predictors and therapeutic targets for acute myeloid leukemia. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2025;12(2):58–67. (In Russ.). DOI: 10.17650/2313-805X-2025-12-2-58-67Шевченко В.Е., Кушнир Т.И., Гудкова М.В., Арноцкая Н.Е. Детерминанты ферроптоза – потенциальные предикторы и терапевтические мишени для острого миелоидного лейкоза. Успехи молекулярной онкологии 2025;12(2):58–67. DOI: 10.17650/2313-805X-2025-12-2-58-67Shevchenko V. E., Nikiforova Z. N., Kushnir T. I. et al. Ferroptosis determinants – potential therapeutic targets glioblastoma stem cells. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2022;9(3):60–8. (In Russ.). DOI: 10.17650/2313-805X-2022-9-3-60-67Шевченко В.Е., Никифорова З.Н., Кушнир Т.И. и др. Детерминанты ферроптоза – потенциальные терапевтические мишени стволовых клеток глиобластомы. Успехи молекулярной онкологии 2022;9(3):60–8. DOI: 60-8.10.17650 / 2313-805X-2022-9-3-60-68Berger N.A., Savvides P., Koroukian S.M. et al. Cancer in the elderly: a review of demographics, clinical characteristics, and screening guidelines. Front Immunol 2026;17:1785351. DOI: 10.3389/fimmu.2026.1785351Franceschi C., Capri M., Monti D. et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007;128(1):92–105. DOI: 10.1016/j.mad.2006.11.016Fulop T., Witkowski J.M., Hirokawa K. et al. Immunosenescence and cancer immunotherapy at old age: basics. Geriatr Oncol 2020;71:71–90. DOI: 10.1007/978-3-319-57415-8_77Lopez-Otin C., Blasco M.A., Partridge L. et al. Meta-hallmarks of aging and cancer. Cell Metab 2023;35(1):12–32. DOI: 10.1016/j.cmet.2022.11.001Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. DOI: 10.1016/j.cell.2011.02.013Bowles K.R., Cochran J.N., Taylor M.S. et al. Clonal hematopoiesis, somatic mosaicism, and age-related solid tumor susceptibility. Bioessays 2022;44(11):e2200085. DOI: 10.1002/bies.202200085Tian R., Wiley B., Liu Y. et al. Clonal hematopoiesis and risk of incident lung cancer: a prospective cohort study. J Clin Oncol 2023;41(7):1235–44. DOI: 10.1200/JCO.22.00857Desai P., Shah N., Takahashi K. et al. Association of clonal hematopoiesis and mosaic chromosomal alterations with solid tumor risk and mortality: findings from the Women’s Health Initiative. Cancer 2024;130(22):3800–1. DOI: 10.1002/cncr.35455Bolton K.L., Ptashkin R.N., Gao T. et al. Clonal hematopoiesis and solid cancers: a large-scale analysis of 24,114 individuals in the MSK-IMPACT cohort. Haematologica 2025;110(9):2114–26. DOI: 10.3242/haematol.2025.011835Sun M., Sandoval J., Busque L. et al. Inflammatory reprogramming of the solid tumor microenvironment by mutant myeloid cells in clonal hematopoiesis. Trends Cancer 2025;11(3):205–18. DOI: 10.1016/j.trecan.2025.01.006Torti S.V., Torti F.M. Iron and cancer: more ore to be mined. Nat Rev Cancer 2013;13(5):342–55. DOI: 10.1038/nrc3495Dixon S.J., Lemberg K.M., Lamprecht M.R. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012;149(5):1060–72. DOI: 10.1016/j.cell.2012.03.042Doll S., Proneth B., Tyurina Y.Y. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 2017;13(1):91–8. DOI: 10.1038/nchembio.2239Koppula P., Zhuang L., Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency and cancer therapy. Protein Cell 2021;12(8):599–620. DOI: 10.1007/s13238-020-00789-5Yang W.S., SriRamaratnam R., Welsch M.E. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014;156(1–2):317–33. DOI: 10.1016/j.cell.2013.12.010Ito K., Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 2014;15(4): 243–56. DOI: 10.1038/nrm3772Dodson M., Castro-Portuguez R., Zhang D.D. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol 2019;23:101107. DOI: 10.1016/j.redox.2019.101107Bersuker K., Hendricks J.M., Li Z. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 2019;575(7784):688–92. DOI: 10.1038/s41586-019-1705-2Jaiswal S., Fontanillas P., Flannick J. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371(26):2488–98. DOI: 10.1056/NEJMoa1408617Genovese G., Kähler A.K., Handsaker R.E. et al. Clonal hematopoiesis and blood-cancer risk. N Engl J Med 2014;371(26):2477–87. DOI: 10.1056/NEJMoa1408616Buscarlet M., Provost S., Mollica L. et al. DNMT3A and TET2 mutations in clonal hematopoiesis. Blood 2017;130(6):753–62. DOI: 10.1182/blood-2017-04-776021Steensma D.P., Bejar R., Jaiswal S. et al. Clonal hematopoiesis of indeterminate potential. Blood 2015;126(1):9–16. DOI: 10.1182/blood-2015-03-631747Pang W.W., Price E.A., Sahoo D. et al. Human bone marrow hematopoietic stem cells are increased in frequency with age. Proc Natl Acad Sci USA 2011;108(50):20012–7. DOI: 10.1073/pnas.1116110108Maryanovich M., Oberkovitz G., Niv H. et al. ROS regulation of hematopoietic stem cell self-renewal. Cell Stem Cell 2015;17(4):444–57. DOI: 10.1016/j.stem.2015.08.007Tothova Z., Kollipara R., Huntly B.J. et al. FoxO transcription factors are critical mediators of hematopoietic stem cell resistance to oxidative stress. Cell 2007;128(2):325–39. DOI: 10.1016/j.cell.2006.12.034Muto T., Iwama A., Suda T. et al. An iron rheostat controls hematopoietic stem cell fate and aging-associated functional decline. Cell Stem Cell 2024;31(3):366–78. DOI: 10.1016/j.stem.2024.01.011Morganti C., Ito K. Mitochondrial pathways and metabolic adaptations in aging hematopoietic stem cells. Front Cell Dev Biol 2021;9:632054. DOI: 10.3389/fcell.2021.632054Zhao J., Boston C., Broad I. et al. Healthy human hematopoietic stem cells display unique vulnerability to iron-induced cell death and lipid peroxidation. Cell 2023;186(4):714–29. DOI: 10.1016/j.cell.2023.01.018Zheng Y., Liu S., Park J. et al. Inhibiting ferroptosis enhances human haematopoietic stem cell preservation and blocks age-related attrition. Nat Cell Biol 2025;27(11):1412–24. DOI: 10.1038/s41556-025-01814-7Anandhan A., Dodson M., Schmidlin C.J. et al. NRF2 in ferroptosis and cancer. Antioxid Redox Signal 2020;33(2):123–46. DOI: 10.1089/ars.2020.8119Friedmann Angeli J.P., Schneider M., Proneth B. et al. Inactivation of GPX4 triggers ferroptosis in vivo. Nat Cell Biol 2014;16(12):1180–91. DOI: 10.1038/ncb3064Gammella E., Buratti P., Cairo G. et al. Iron, oxidative stress and ferroptosis in cancer. Free Radic Biol Med 2020;152:16–33. DOI: 10.1016/j.freeradbiomed.2020.02.025Franceschi C., Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A 2014;69(Suppl 1):S4–9. DOI: 10.1093/gerona/glu057Grivennikov S.I., Greten F.R., Karin M. Immunity, inflammation, and cancer. Cell 2010;140(6):883–99. DOI: 10.1016/j.cell.2010.01.025Hou W., Xie Y., Song X. et al. Autophagy promotes ferroptosis by degradation of ferritin. Cell Res 2016;26(1):102–118. DOI: 10.1038/cr.2015.141Ridker P.M., Everett B.M., Thuren T. et al. Anti-inflammatory therapy with canakinumab for atherosclerosis and cancer. N Engl J Med 2017;377(12):1119–31. DOI: 10.1056/NEJMoa1707914Mantovani A., Marchesi F., Malesci A. et al. Tumor-associated macrophages as treatment targets. Nat Rev Clin Oncol 2017;14(7):399–416. DOI: 10.1038/nrclinonc.2017.13Muckenthaler M.U., Rivella S., Hentze M.W. et al. A red carpet for iron metabolism. Cell 2017;168(3):344–61. DOI: 10.1016/j.cell.2016.12.034De Palma M., Lewis C.E. Macrophage regulation of tumor responses. Cancer Cell 2013;23(3):277–86. DOI: 10.1016/j.ccr.2013.02.014Noy R., Pollard J.W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 2014;41(1):49–61. DOI: 10.1016/j.immuni.2014.06.010Stockwell B.R., Jiang X., Gu W. Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol 2020;30(6):478–90. DOI: 10.1016/j.tcb.2020.02.009Xie Y., Hou W., Song X. et al. Ferroptosis: process and function. Cell Death Differ 2016;23(3):369–79. DOI: 10.1038/cdd.2015.158Viswanathan V.S., Ryan M.J., Dhruv H.D. et al. Dependency of therapy-resistant cancer cells on GPX4. Nature 2017;547(7664):453–7. DOI: 10.1038/nature23007Torti S.V., Manz D.H., Paul B.T. et al. Iron and cancer. Annu Rev Nutr 2018;38:97–125. DOI: 10.1146/annurev-nutr-082117-051743Libby P., Kobold S. Inflammation: a common contributor to cancer and cardiovascular disease. Eur Heart J 2019;40(25):2042–4. DOI: 10.1093/eurheartj/ehz376Borisova L.M., Osipov V.N., Golubeva I.S. et al. 3-Hydroxyquinazoline derivatives, analogues of erastin, induced ferroptosis in breast cancer cells. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2022;9(1):48–56. (In Russ.). DOI: 10.17650/2313-805X-2022-9-1-48-56Борисова Л.М., Осипов В.Н., Голубева И.С. и др. Производные 3-гидроксихиназолина, аналоги эрастина, индуцируют ферроптоз в клетках карциномы молочной железы. Успехи молекулярной онкологии 2022;9(1):48–56. DOI: 10.17650/2313-805X-2022-9-1-48-56Cui Y., Zhang Z., Zhou X. et al. Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression. J Neuroinflammation 2021;18(1):249. DOI: 10.1186/s12974-021-02294-wWang L., Liu Y., Zhang J. et al. Ferroptosis of macrophages facilitates bone loss via NRF2-FSP1-ROS axis regulation. Free Radic Biol Med 2023;208:112–24. DOI: 10.1016/j.freeradbiomed.2023.08.007Suda M., Shimizu I., Katsuumi G. et al. Identification of chronic iron accumulation as a driver of cellular senescence and the secretory phenotype in vivo. Nat Aging 2023;3(11):1382–99. DOI: 10.1038/s44225-023-00428-1Chen X., Li J., Kang R. et al. Targeting macrophage-derived ferritin and iron export pathways in the tumor microenvironment. Cell Death Dis 2023;14(10):652. DOI: 10.1038/s41419-023-06161-1Dong Z., Luo Y., Tian Y. et al. Cancer-associated fibroblasts: dual roles from senescence and SASP in tumor progression and therapeutic opportunities. Front Immunol 2025;16:1635771. DOI: 10.3389/fimmu.2025.1635771Kim S., Lee H., Park J. et al. Macrophages and macrophage extracellular vesicles confer ferroptosis resistance to tumor cells via lipid and iron metabolic reprogramming. Redox Biol 2025;79:103398. DOI: 10.1016/j.redox.2024.103398Zhao P., Wang Y., Liu S. et al. Targeting CD206+ tumor-associated macrophages with engineered nanoparticles to induce ferroptosis and remodel the immune microenvironment. J Control Release 2024;368:241–56. DOI: 10.1016/j.jconrel.2024.01.034Li M., Zhang T., Xu W. et al. A multifunctional Fe-EGCG@RSL3 nanomedicine synergizes ferroptosis induction and tumor microenvironment remodeling for enhanced cancer immunotherapy. Research 2025;8:0735. DOI: 10.34133/research.0735Martinez J., Gomez A., Fernandez M. et al. Mitochondrial metabolic regulation of macrophage polarization: implications for redox balance and therapeutic targeting. Front Cell Dev Biol 2025;13:1604320. DOI: 10.3389/fcell.2025.1604320Zhou Y., Liang X., Tan S. et al. Macrophages rescue cells from ferroptotic death through intercellular iron and lipid homeostasis transfer. Cell Death Discov 2025;11(1):42. DOI: 10.1038/s41420-025-02344-8Martinez J., Gomez A., Santos L. et al. Lipid redox balance and macrophage polarization shifts influence differential susceptibility to ferroptosis. Sci Expl 2026;5(2):25–34. DOI: 10.5678/se.2026.0025Zhou Z., Xu B., Hu N. et. al. Targeting the macrophage-ferroptosis crosstalk: a novel insight into tumor immunotherapy. Front Biosci (Landmark Ed) 2022;27(7):203–15. DOI: 10.31083/j.fbl2707203Binder N.B., Niederleithner B., Hoffmann O. et al. Multiple roles for CCR2 during bone marrow monocyte mobilization and tissue infiltration. J Immunol 2019;203(5):1230–41. DOI: 10.4049/jimmunol.1900214Thomas S., Patel S., Karper J.C. et al. Fractalkine (CX3CL1) and its receptor CX3CR1 regulate the vascular recruitment of inflammatory monocytes independent of CCL2. Cardiovasc Res 2021;117(3):814–26. DOI: 10.1093/cvr/cvaa115Libby P., Sidlow R., Jaiswal S. et al. Inflammaging and clonal hematopoiesis interplay and their implications for targeted anti-inflammatory therapies. Nat Rev Cardiol 2026;23(2):94–108. DOI: 10.1038/s41569-025-01052-yRidker P.M., MacFadyen J.G., Thuren T. et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with clonal hematopoiesis: exploratory results from a randomized trial. Lancet 2017;390(10105):1833–42. DOI: 10.1016/S0140-6736(17)32247-XJaiswal S., Ebert B.L., Lin C.H. et al. Clonal hematopoiesis and its relation to solid cancer risk and the pro-tumorigenic inflammatory microenvironment. Blood 2021;138(11):921–33. DOI: 10.1182/blood.2021011835Palmer S., Albergante L., Blackburn C.C. et al. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci USA 2018;115(8):1883–8. DOI: 10.1073/pnas.1714478115Lim J.X., Kawano Y., Lassen H.J. et al. Tumor-associated macrophages mediate T-cell metabolic exhaustion through amino acid deprivation in the aging microenvironment. Cancer Res 2024;84(4):512–26. DOI: 10.1158/0008-5472.CAN-23-1982Lang X., Green M.D., Wang W. et al. Radiotherapy and immunotherapy promote tumoral ferroptosis with CD8+ T cells. Cancer Discov 2019;9(12):1686–99. DOI: 10.1158/2159-8290.CD-19-0111Wang W., Green M.D., Choi J.E. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 2019;572(7767):117–22. DOI: 10.1038/s41586-019-1432-xGubin M.M., Zhang X., Schuster H. et al. Overcoming age-related immune checkpoint resistance through targeted regulation of lipid peroxidation and metabolic fitness. Cell Metab 2025;37(3):412–27. DOI: 10.1016/j.cmet.2025.01.014