Cited by 515Iron Metabolism and DisordersFerroptosis and cancer prognosisTrace Elements in Health

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Iron and cancer: recent insights

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Manz, David H., Blanchette, Nicole L., Paul, Bibbin T., Torti, Frank M., Torti, Suzy V.·2016·Annals of the New York Academy of Sciences

DOI 10.1111/nyas.13008PMC PMC4870095

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Abstract

Iron is an essential dietary element. However, the ability of iron to cycle between oxidized and reduced forms also renders it capable of contributing to free radical formation, which can have deleterious effects, including promutagenic effects that can potentiate tumor formation. Dysregulation of iron metabolism can increase cancer risk and promote tumor growth. Cancer cells exhibit an enhanced dependence on iron relative to their normal counterparts, a phenomenon we have termed iron addiction. Work conducted in the past few years has revealed new cellular processes and mechanisms that deepen our understanding of the link between iron and cancer. Control of iron efflux through the combined action of ferroportin, an iron efflux pump, and its regulator hepcidin appears to play an important role in tumorigenesis. Ferroptosis is a form of iron‐dependent cell death involving the production of reactive oxygen species. Specific mechanisms involved in ferroptosis, including depletion of glutathione and inhibition of glutathione peroxidase 4, have been uncovered. Ferritinophagy is a newly identified mechanism for degradation of the iron storage protein ferritin. Perturbations of mechanisms that control transcripts encoding proteins that regulate iron have been observed in cancer cells, including differences in miRNA, methylation, and acetylation. These new insights may ultimately provide new therapeutic opportunities for treating cancer.

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Background
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Background
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BackgroundInfluential
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“Serum hepcidin levels are elevated in many cancers, including hepatocellular carcinoma, prostate, breast, multiple myeloma, ovarian cancers, non-Hodgkin lymphoma, and gastrointestinal cancers (34–40).”
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Background
A multiomic ferroptosis-associated prognostic signature incorporating epigenetic and transcriptional biomarkers for hepatocellular carcinoma
Chen, J., Zhu, X., Chen, D., Jin, L., Xu, W., Yu, W., & Zhang, L. (2022) · Translational Cancer Research · doi:10.21037/tcr-21-2882 · Cited by 3
“Previous studies suggested that targeting ferroptosis-related genes could sensitizing cancer cells to ferroptosis and subsequently suppressing tumor growth in HCC (10-12).”
Environmental insults and compensative responses: when microbiome meets cancer
Nagpal, S., & Mande, S. S. (2023) · Discover Oncology · doi:10.1007/s12672-023-00745-9 · Cited by 4
“This can reciprocate nutrient stress on cancer (Figure 3), limiting its proliferation by competing for the nutrients critical for tumor progression, particularly BCAA, acetate and iron [61 – 63].”
Background
Anticancer Activities of Ferrous and Ferric Ions in Progression, Proliferation, Angiogenesis, Invasion and Metastasis against Cancer and Tumor Cells
Ishida, T. (2018) · doi:10.5281/zenodo.18907818 · Cited by 4
Proteomic Profiling of Iron‐Treated Ovarian Cells Identifies AKT Activation that Modulates the CLEAR Network
Rockfield, S., Guergues, J., Rehman, N., Smith, A., Bauckman, K., Stevens, S. M., & Nanjundan, M. (2018) · PROTEOMICS · doi:10.1002/pmic.201800244 · Cited by 5
Iron Support in Erythropoietin Treatment in Myelodysplastic Syndrome Patients Affected by Low-Risk Refractory Anaemia: Real-Life Evidence from an Italian Setting
Giordano, G., Cutuli, M. A., Lucchesi, A., Magnifico, I., Venditti, N., Vergalito, F., Gasperi, M., & Marco, R. D. (2019) · Acta Haematologica · doi:10.1159/000501329 · Cited by 4
Influence of plant-derived bioactive compounds on iron metabolism: mechanistic insights with translational relevance
Freitas, S. M. D. L., Menezes, M. C. D. S., Soares, C. L., Batista, M. D. S., da Costa, D. C. F., Omena, J., & Citelli, M. (2025) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2025.2540043 · Cited by 4
“Cancer cells are characterized by elevated basal reactive oxygen species (ROS), enhanced iron uptake, larger labile iron pools (LIP), and dysregulated antioxidant defense mechanisms (Manz et al. 2016).”
FSP1, a key ferroptosis suppressor with therapeutic potential
Bai, X., Zhu, J., Xiong, B., Chen, Y., Xu, C., Zhao, Q., Wu, Y., Tang, Z., Shi, R., Liu, Z., et al. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118151 · Cited by 3
Glucose increases proliferation and chemoresistance in chronic myeloid leukemia via decreasing antioxidant Properties of ω-3 polyunsaturated fatty acids in the presence of Iron
Shahraki, S., Bahraini, F., Mesbahzadeh, B., Sayadi, M., & Sajjadi, S. M. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08891-7 · Cited by 3
“Additionally, the dependence of the ribonucleotide reductase on iron for DNA synthesis demonstrates the significance of iron in the development and rapid proliferation of leukemia cells [24].”
Background
Ferroptosis in immune chaos: Unraveling its impact on disease and therapeutic potential
Direksunthorn, T., Ahmed, A. T., Pluetrattanabha, N., Uthirapathy, S., Ballal, S., Singh, A., Al‐Hetty, H. R. A. K., Devi, A., Sharma, G. C., & Yumashev, A. V. (2025) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-025-01078-7 · Cited by 4
Yeni Bir Hücre Ölüm Şekli Olarak Ferroptozis
Çelenk, A. (2021) · Arşiv Kaynak Tarama Dergisi · doi:10.17827/aktd.980659 · Cited by 3
Development and validation of a prognostic prediction model for iron metabolism-related genes in patients with pancreatic adenocarcinoma
Wei, W., Cao, B., Xu, D., Liu, Y., Zhang, X., & Wang, Y. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2022.1058062 · Cited by 3
“Control of iron metabolism is fundamental to almost all known life, meanwhile, iron metabolism is also considered indispensable for cancer development (Manz et al., 2016).”
Background
Structure and potential applications of bacterial siderophores
Haseeb, M., Shafiq, M., Noman, F., Hamna, Mahrukh, M., Abbas, S. A. A. A., & Ali, N. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-95251-4.00007-7 · Cited by 3
Synthesis and preclinical evaluation of [18F]AlF-NODA-MP-C6-CTHRSSVVC as a PET tracer for CD163-positive tumor-infiltrating macrophages
Fernandes, B., Antunes, I. F., Prasad, K., Vazquez-Matias, D. A., de Mattos, E. P., Szymański, W., Jeckel, C. M. M., de Vries, E. F. J., & Elsinga, P. H. (2024) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2024.108946 · Cited by 3
Tissue inhibitor of metalloproteinase 1 promotes ferroptosis and suppresses prostate cancer metastasis
Rao, Y., Pan, Q., Liu, S., Yao, S., Li, L., Yan, J., Chen, L., Xu, L. L., Yan, H., Ma, A., et al. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108473 · Cited by 3
Anticoagulation, ferrotoxicity and the future of translational lung cancer research
Zacharski, L. R. (2016) · Translational Lung Cancer Research · doi:10.21037/tlcr.2016.05.06 · Cited by 3
Myelolipoma among patients with thalassemia major and rare anemia with iron loading: A not so rare entity
Ricchi, P., Costantini, S., Spasiano, A., Matola, T. D., Cinque, P., & Filosa, A. (2016) · American Journal of Hematology · doi:10.1002/ajh.24622 · Cited by 3
“However, further studies are also needed to fully evaluate adrenal steroid secretion and hypothalamicpituitary-adrenal (HPA) axis function in TM patients and to clarify if iron per se could also play a role in myelolipoma formation.(5) In conclusion, myelolipoma appears to be an emerging entity among TM patients and p…”
Background
CISD3 is required for Complex I function, mitochondrial integrity, and skeletal muscle maintenancePreprint
Marjault, H., Karmi, O., Rowland, L. M., Nguyen, T. T., Grant, D. G., Manrique‐Acevedo, C., Nechushtai, R., & Mittler, R. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.03.543558 · Cited by 3
Artesunate alleviates radiation‐induced submandibular gland epithelial cell damage in rats by reducing inflammation and apoptosis
Wang, Y., Zhao, D., & Nong, X. (2024) · Cell Biology International · doi:10.1002/cbin.12261 · Cited by 2
“Cancer cells exhibit a heightened dependence on iron for growth and are significantly more susceptible to iron depletion compared to noncancer cells (Manz et al., 2016).”
The effectiveness of sanggenon c in alleviating SLC7A11-induced ferroptosis in lung cancer was evaluated using in vivo, in vitro, and computational approaches
Liu, Y., Tang, A., Liu, M., Luo, Z., Cao, F., & Yang, C. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113819 · Cited by 2
Synergistic bioinformatics and sophisticated machine learning unveil ferroptosis-driven regulatory pathways and immunotherapy potential in breast carcinoma
Xia, L., Ye, Z., Zheng, M., & Tan, Z. (2025) · Discover Oncology · doi:10.1007/s12672-025-02393-7 · Cited by 2
“Recent advances have highlighted innovative approaches to induce ferroptosis, including the use of an Fe 2 ⁺ -anchored metal–organic framework designed to selectively deliver Fe 2 ⁺ ions into cancer cells [14].”
Mechanism and importance of ferroptosis in clear cell renal cell carcinoma treatment
Neeraj, M. A., Noh, S., Chae, J., & Choi, J. (2025) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2025.105004 · Cited by 2
Prokaryotic organelle mitochondria drive tumorigenesis: “the original sin”
Wang, C., Luo, M., Zhou, J., Zhang, Q., Xiawei, J., He, J., Wang, L., Huang, Y., Xu, X., & 王方岩 (2026) · Frontiers in Oncology · doi:10.3389/fonc.2025.1632702 · Cited by 3
Short‐Chain Fatty Acids Modulate Iron Metabolism and Induce Oxidative Stress and Ferroptosis in Breast Cancer Cells
Rah, B., Shafarin, J., Janeeh, A. S., Rafiq, R., Kurabi, T. M., Muhammad, J. S., Elkord, E., & Hamad, M. A. (2026) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.70771 · Cited by 2
“This pattern indicates a metabolic shift toward enhanced iron acquisition and retention within tumor cells, consistent with previous reports linking iron overload to tumorigenic signaling, oxidative stress tolerance, and metabolic reprogramming [23, 24].”
Proteomic landscape of Ewing sarcoma primary tumors and metastases
Gordon, S., Mohan, V., Shukrun, R., Golani, O., Metzger, S., Sher, O., Manisterski, M., Oren, R., Fellus-Alyagor, L., Beck, L., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70449-5 · Cited by 2
Cyanide Bridged Platinum‐Iron Complexes as Cisplatin Prodrug Systems: Design and Computational Study
Kaspi, A. W., Bhandari, S., Schubert, A., Huang, S. D., & Dunietz, B. D. (2020) · ChemPhysChem · doi:10.1002/cphc.202000748 · Cited by 2
Impact of allogeneic red blood cell transfusion on prognosis in soft tissue sarcoma patients. A single‐centre study
Smolle, M. A., Helmberg, W. M. C., Matzhold, E. M., Barth, D. A., Sareban, N., Szkandera, J., Liegl‐Atzwanger, B., Leithner, A., & Pichler, M. (2022) · Cancer Medicine · doi:10.1002/cam4.4989 · Cited by 2
Emerging Role of Ferroptosis in Breast Cancer: Characteristics, Therapy, and Translational Implications for the Present and Future
Ray, S. K., & Mukherjee, S. (2023) · Current Molecular Medicine · doi:10.2174/1566524023666230913105735 · Cited by 2
Impact on oxidative stress of oral, high-dose, iron supplementation for management of iron deficiency after bariatric surgery, a preliminary study
Babayev, M., Klaunig, J. E., Silveyra, P., Henschel, B., & Gletsu-Miller, N. A. (2023) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2023.127310 · Cited by 2
Identification of new hub- ferroptosis-related genes in Lupus Nephritis
Zheng, X., Chen, Y., Li, Y., Li, X.-L., Sun, D., & Li, Y.-Q. (2024) · Autoimmunity · doi:10.1080/08916934.2024.2319204 · Cited by 3
“Altogether, we discuss some of the above candidates FRGs-LN in the function of ferroptosis, others are also famous during the course, such as p53 being involved in polyamine metabolism, which affects cellular growth, development, and programmed cell death [70].”
Hepcidin: A potent antimicrobial peptide involved in iron homeostasis
Soofiyani, S. R., Soltani, E., Nejad, M. K., Ghanbari, R., & Memar, M. Y. (2024) · Gene Reports · doi:10.1016/j.genrep.2024.102082 · Cited by 3
The marine xanthophyll diatoxanthin as ferroptosis inducer in MDAMB231 breast cancer cells
Sansone, C., Pistelli, L., & Brunet, C. (2025) · Scientific Reports · doi:10.1038/s41598-025-91519-6 · Cited by 2
“Dt induces FTH1/FTL1 degradation through the overexpression of nuclear receptor coactivator 4 (NCOA4) and the activation of autophagy protein 5 (ATG5) and autophagy protein 7 (ATG7).”
Ferroptosis in Cancer Disease
Hassannia, B., & Berghe, T. V. (2019) · Springer eBooks · doi:10.1007/978-3-030-26780-3_17 · Cited by 2
Tumoral Overexpression of Hepcidin is Associated with Poor Prognosis of Patients with Clear Cell Renal Cell Carcinoma
Qiu, H., Gu, G., Zuo, E., & Cheng, X. (2022) · Cancer Investigation · doi:10.1080/07357907.2022.2133775 · Cited by 2
“HAMP generated by cancer cells binds to FPN and initiates local autocrine signaling to degrade FPN, leading to increased intracellular iron concentration (31).”
Background
Hepcidin as a prognostic biomarker in clear cell renal cell carcinoma.
Zhou, Z., Wu, J., Yang, Y., Gao, P., Wang, L., & Wu, Z. (2022) · PubMed Central · Cited by 2
Potential Key Markers for Predicting the Prognosis of Gastric Adenocarcinoma based on the Expression of Ferroptosis Related LncRNAPreprint
Cai, Y., Wu, S., Yifan, J., Pan, X., & Li, C. (2021) · Research Square · doi:10.21203/rs.3.rs-827082/v1 · Cited by 2
A novel ferroptosis-related 12-gene signature predicts clinical prognosis and reveals immune relevancy in clear cell renal cell carcinomaPreprint
Hong, Y., Lin, M., Ou, D., Huang, Z., & Shen, P. (2021) · doi:10.21203/rs.3.rs-153932/v1 · Cited by 2
The Effectiveness of a Nursing Care Program Supplemented with Iron Intake on Anemia and Fatigue in Cancer Patients Undergoing Chemotherapy
Barahoui, Z., Kiyani, F., Lashkari, T., & Tasbandi, M. (2020) · Medical - Surgical Nursing Journal · doi:10.5812/msnj.111464 · Cited by 1
“One of the essential interventions in the treatment of anemia is iron supplementation (23).”
Background
Does eating fish cause cancer? A case study metal(loid)s accumulation in mackerel and sardine tissues from İskenderun Bay, Türkiye
Ergen, Ş. F., Altındağ, A., & Baş, Y. S. (2023) · Environmental Monitoring and Assessment · doi:10.1007/s10661-023-11779-5 · Cited by 1
“Thus, impaired iron metabolism is also likely to increase the risk of cancer (Manz et al., 2016).”
Background
The Potential Role of Non-coding RNAs in Regulating Ferroptosis in Cancer: Mechanisms and Application Prospects
Cao, M., Zhang, Z., Hou, X.-R., & Wang, X. (2024) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/0118715206322163240710112404 · Cited by 1
Exploring modifiable risk factors: insights from Mendelian randomization analyses of gastric cancer in East Asian populations
He, W., Tan, X., Yang, W., Huang, D., Zhang, H., & Liu, H. (2025) · Discover Oncology · doi:10.1007/s12672-025-01953-1 · Cited by 1
“Recent views suggest that dysregulation of iron metabolism increases cancer risk and promotes tumor growth, and perturbations in the mechanisms controlling transcripts of iron-regulated proteins, including differences in miRNA, methylation, and acetylation, have been observed in cancer cells [25].”

Authors: Manz, D. H., Blanchette, N. L., Paul, B. T., Torti, F. M., & Torti, S. V.
Affiliations: Department of Molecular Biology and Biophysics
UConn Health (US)
Corresponding author: Torti, Suzy V.
ORCID: Torti, Frank M.
Torti, Suzy V.
Venue: Annals of the New York Academy of Sciences
Publisher: Wiley
Published: 2016-02-18
Volume: 1368
Issue: 1
Pages: 149-161
ISSN: 0077-8923 (ISSN-L)
1749-6632
DOI: 10.1111/nyas.13008
PMC: PMC4870095
OpenAlex: W2275201610
Cited by: 507
References: 121
Citations by year: 2026: 24 · 2025: 49 · 2024: 69 · 2023: 78 · 2022: 66 · 2021: 77 · 2020: 46 · 2019: 43 · 2018: 31 · 2017: 14 · 2016: 10
FWCI: 4.64
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Annals of the New York Academy of Sciences (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: S.V.T (CA188025)
F.M.T (CA171101)
D.H.M. (DE021989)
U.S. National Institutes of Health
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords: iron metabolism, cancer, ferroptosis, ferroportin, hepcidin, iron efflux, reactive oxygen species, glutathione depletion, GPX4, ferritinophagy, ferritin degradation, tumor microenvironment, epigenetic regulation, microRNA, DNA methylation, histone acetylation, cancer therapy
MeSH terms: Ferroportin, Animals, Humans, Iron, Neoplasms, Reactive Oxygen Species, Iron Overload, Cation Transport Proteins

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