Iron and cancer: recent insights

Manz, David H.; Blanchette, Nicole L.; Paul, Bibbin T.; Torti, Frank M.; Torti, Suzy V.

doi:10.1111/nyas.13008

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

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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Cancer cells need large amounts of readily available labile Fe2+ to survive and grow.
“cancer cells have a high demand for easily accessible labile Fe2+ for their survival and growth.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [23]

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[114]Sangokoya 2013 Iron-Responsive miR-485-3p Regulates Cellular Iron Homeostasis by Targeting Ferroportin PLoS Genet 9 e1003408 23593016 PMC3616902

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Rochette, L., Dogon, G., Rigal, E., Zeller, M., Cottin, Y., & Vergely, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010449 · Cited by 932 · see citing works
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Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis
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“ted that cancer cells exhibit higher iron retention than their nonmalignant counterparts [11,167].”
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GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis
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“This phenomenon has been termed iron addiction [25].”
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“which consequently demands a greater amount of iron and results in dysregulated levels of key proteins involved in iron metabolism [38, 39].”
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Tumor heterogeneity in autophagy-dependent ferroptosis
Li, J., Liu, J., Xu, Y., Wu, R., Chen, X., Song, X., Zeh, H. J., Kang, R., Klionsky, D. J., Wang, X., et al. (2021) · Autophagy · doi:10.1080/15548627.2021.1872241 · Cited by 246 · see citing works
“SLC40A1 emerges as a critical regulator of tumor growth and progression in multiple cancer types by regulating iron homeostasis [64].”
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Identification of Frataxin as a regulator of ferroptosis
Du, J., Zhou, Y., Li, Y., Xia, J., Chen, Y., Chen, S., Wang, X., Sun, W., Wang, T., Ren, X., et al. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101483 · Cited by 243 · see citing works
“Interestingly, relative to healthy cells, cancer cells do exhibit an enhanced dependence on iron to enable its growth, which may act as a target for cancer therapy [3].”
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The ferroptosis and iron-metabolism signature robustly predicts clinical diagnosis, prognosis and immune microenvironment for hepatocellular carcinoma
Tang, B., Zhu, J., Li, J., Fan, K. C., Gao, Y., Cheng, S., Kong, C., Zheng, L., Wu, F., Weng, Q., et al. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00663-1 · Cited by 217 · see citing works
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NEET Proteins: A New Link Between Iron Metabolism, Reactive Oxygen Species, and Cancer
Mittler, R., Darash‐Yahana, M., Sohn, Y. S., Bai, F., Song, L., Cabantchik, I. Z., Jennings, P. A., Onuchic, J. N., & Nechushtai, R. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7502 · Cited by 188 · see citing works
“The iron addiction phenotype of cancer cells (9, 47, 49, 68, 69) and the enhanced levels of ROS cancer cells generate (8, 18, 29, 58, 60) could suggest that NEET proteins are involved in the protection of mitochondria from iron and ROS over-accumulation in tumors.”
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Nanomaterial-induced ferroptosis for cancer specific therapy
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“It is unclear if an imbalance in the Mn to Fe ratio in the mitochondrial matrix is a contributing factor to the regulation of SOD2 activity in cancer; however, it is well known that Fe imbalance and altered expression of iron transport proteins, such as the transferrin receptor, is a phenotype of cancer cells and can…”
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A promising new approach to cancer therapy: Targeting iron metabolism in cancer stem cells
El-Hout, M., Santos, L. D., Hamaï, A., & Mehrpour, M. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.07.009 · Cited by 170 · see citing works
“Transferrin (Tf) transferrin receptor 1 (TFR1), metalloreductase STEAP family member 3 (STEAP3), labile iron pool (LIP), poly rC-binding proteins (PCBPs), ferroportin (FPN1), ceruloplasmin (CP), and hephaestin (HEPH).”
BackgroundInfluential
Iron and leukemia: new insights for future treatments
Wang, F., Lv, H., Zhao, B., Zhou, L., Wang, S., Luo, J., Liu, J., & Shang, P. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1397-3 · Cited by 170 · see citing works
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“Data from epidemiological studies and animal models have raised some concerns regarding the possible role of deregulated iron metabolism in certain cancer types [96,97], including promotion of tumor growth and enhanced oxidative stress [98].”
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The Relationship between Ferroptosis and Tumors: A Novel Landscape for Therapeutic Approach
Xia, X., Fan, X., Zhao, M., & Zhu, P. (2019) · Current Gene Therapy · doi:10.2174/1566523219666190628152137 · Cited by 159 · see citing works
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“The important role of miRNAs in regulating iron homeostasis has been reviewed well before (77), including regulating proteins that control the iron export, import and storage.”
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The Role of Iron in Cancer Progression
Guo, Q., Li, L., Hou, S., Yuan, Z., Li, C., Zhang, W., Zheng, L., & Li, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.778492 · Cited by 150 · see citing works
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Activation of NRF2/FPN1 pathway attenuates myocardial ischemia–reperfusion injury in diabetic rats by regulating iron homeostasis and ferroptosis
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“Furthermore, related research has shown that supply of exogenous iron such as ferric ammonium citrate, ammonium citrate, and ferric citrate can enhance the ferroptosis induced by erastin and RSL3 (Manz et al.”
Background
Neoadjuvant Chemotherapy Shifts Breast Tumor Microbiota Populations to Regulate Drug Responsiveness and the Development of Metastasis
Chiba, A., Bawaneh, A., Velázquez, C., Clear, K. Y. J., Wilson, A. S., Howard-McNatt, M. M., Levine, E. A., Levi‐Polyachenko, N. H., Yates-Alston, S. A., Diggle, S. P., et al. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-19-0451 · Cited by 145 · see citing works
“Cancer cells exhibit “iron addiction” and therapies to reduce iron levels were previously shown to suppress breast tumor growth (30, 31), suggesting another possible molecular mechanism by which Pseudomonas secreted compounds may potentiate chemotherapy responsiveness.”
Background
Erastin, a ferroptosis-inducing agent, sensitized cancer cells to X-ray irradiation via glutathione starvation in vitro and in vivo
Shibata, Y., Yasui, H., Higashikawa, K., Miyamoto, N., & Kuge, Y. (2019) · PLoS ONE · doi:10.1371/journal.pone.0225931 · Cited by 145 · see citing works
Iron metabolism and its contribution to cancer (Review)
Chen, Y., Fan, Z., Yang, Y., & Gu, C. (2019) · International Journal of Oncology · doi:10.3892/ijo.2019.4720 · Cited by 142 · see citing works
“Ferroptosis may be triggered by erastin, sorafenib and sulfasalazine (5,146).”
Background
Ironing out mechanisms of iron homeostasis and disorders of iron deficiency
Koleini, N., Shapiro, J. S., Geier, J., & Ardehali, H. (2021) · Journal of Clinical Investigation · doi:10.1172/jci148671 · Cited by 145 · see citing works
“The treatment of ID with iron in the setting of malignancy is complicated by the differential effects of iron on erythropoiesis versus the malignancy itself (131).”
Background
Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo
Xia, Y., Liu, S., Li, C., Ai, Z., Shen, W., Ren, W., & Yang, X. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03194-2 · Cited by 135 · see citing works
Ferroptosis: An emerging approach for targeting cancer stem cells and drug resistance
Elgendy, S. M., Alyammahi, S. K., Alhamad, D. W., Abdin, S. M., & Omar, H. A. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.103095 · Cited by 133 · see citing works
FTH promotes the proliferation and renders the HCC cells specifically resist to ferroptosis by maintaining iron homeostasis
Hu, W., Zhou, C., Jing, Q., Li, Y., Yang, J., Yang, C., Wang, L., Hu, J., Li, Y., Wang, H., et al. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02420-x · Cited by 133 · see citing works
“As previously mentioned, amplifying cancer cells exhibit more dependence on iron than the non-malignant cells, which is termed iron addiction [14], revealing an appealing therapeutic approach for triggering ferroptosis in iron-rich tumors.”
Background
A review of the concepts, recent advances and niche applications of the (photo) Fenton process, beyond water/wastewater treatment: Surface functionalization, biomass treatment, combatting cancer and other medical uses
Giannakis, S. (2019) · Applied Catalysis B: Environmental · doi:10.1016/j.apcatb.2019.02.025 · Cited by 132 · see citing works
Saponin Formosanin C-Induced Ferritinophagy and Ferroptosis in Human Hepatocellular Carcinoma Cells
Lin, P.-L., Tang, H. F., Wu, S., Shaw, N.-S., & Su, C. (2020) · Antioxidants · doi:10.3390/antiox9080682 · Cited by 129 · see citing works
“It is noteworthy that the overexpression of ferritin has been observed in hepatocellular cancer, and FPN is significantly diminished in hepatocellular cancer cells as compared to their normal counterparts [6].”
Background
Hypoxic tumor therapy by hemoglobin-mediated drug delivery and reversal of hypoxia-induced chemoresistance
Yang, J., Li, W., Luo, L., Jiang, M., Zhu, C., Qin, B., Yin, H., Yuan, X., Yin, X., Zhang, J., et al. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.08.004 · Cited by 126 · see citing works
Ferritinophagy: research advance and clinical significance in cancers
Wang, J., Wu, N., Peng, M., Oyang, L., Jiang, X., Peng, Q., Zhou, Y., He, Z., & Liao, Q. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01753-y · Cited by 128 · see citing works
“…family member 4, regulator of G-protein signaling 4, single stranded DNA binding protein 1 (SSBP1) [28], it has been observed that ferritinophagy controls disturbed protein mechanisms encoding and regulating iron transcripts, including differences in miRNA, methylation and acetylation [29].”
Background
Cancer-associated fibroblasts impair the cytotoxic function of NK cells in gastric cancer by inducing ferroptosis via iron regulation
Yao, L., Hou, J., Wu, X., Lu, Y., Jin, Z., Yu, Z., Yu, B., Li, J., Yang, Z., Li, C., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102923 · Cited by 125 · see citing works
“Dysregulated iron metabolism is a hallmark of many cancers [21,22] and is manifested as iron overload in the TME [23,24].”
Background
Inhibition of CISD2 promotes ferroptosis through ferritinophagy-mediated ferritin turnover and regulation of p62–Keap1–NRF2 pathway
Li, Y., Xu, B., Ren, X., Wang, L., Xu, Y., Zhao, Y., Yang, C., Chen, Y., Li, Y., Tong, X., et al. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00383-z · Cited by 119 · see citing works
Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling
Koeberle, S. C., Kipp, A. P., Stuppner, H., & Koeberle, A. (2023) · Medicinal Research Reviews · doi:10.1002/med.21933 · Cited by 115 · see citing works
“the Fenton reaction effectively trigger lipid peroxidation, preferentially induce ferroptosis as compared to other cell death programs, and might show selectivity for cancer cells due to higher iron levels in tumors as compared to healthy tissue.(124,125) Even general ROS inducers might have some preference for cancer…”
Background
The effect of abnormal iron metabolism on osteoporosis
Che, J., Yang, J., Zhao, B., Zhang, G., Wang, L., Peng, S., & Shang, P. (2020) · Biological Trace Element Research · doi:10.1007/s12011-019-01867-4 · Cited by 113 · see citing works
The role of ferroptosis in breast cancer patients: a comprehensive analysis
Wu, Z., Tang, Y., Yu, H., & Li, H. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00473-5 · Cited by 110 · see citing works
Gene interfered-ferroptosis therapy for cancers
Gao, J., Luo, T., Wang, J., & Wang, J. (2021) · Nature Communications · doi:10.1038/s41467-021-25632-1 · Cited by 109 · see citing works
Dysregulation of iron metabolism in cancer stem cells
Recalcati, S., Gammella, E., & Cairo, G. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.07.015 · Cited by 107 · see citing works
DDX17 induces epithelial-mesenchymal transition and metastasis through the miR-149-3p/CYBRD1 pathway in colorectal cancer
Zhao, G., Wang, Q., Zhang, Y., Gu, R. C., Liu, M., Li, Q., Zhang, J., Yuan, H., Feng, T., Ou, D., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-022-05508-y · Cited by 103 · see citing works
Alterations in Cellular Iron Metabolism Provide More Therapeutic Opportunities for Cancer
Zhou, L., Zhao, B., Zhang, L., Wang, S., Dong, D., Lv, H., & Shang, P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051545 · Cited by 102 · see citing works
Iron Metabolism in Cancer Progression
Forciniti, S., Greco, L., Grizzi, F., Malesci, A., & Laghi, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21062257 · Cited by 101 · see citing works
“Various iron-related proteins have been related to cancer progression and metastasis, having an altered expression and activity in cancer cells compared with the normal counterpart [13].”
Background
Role of ferroptosis in neurological diseases
Yao, M.-Y., Liu, T., Zhang, L., Wang, M., Yang, Y., & Gao, J. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2020.135614 · Cited by 100 · see citing works
HO‐1 Contributes to Luteolin‐Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation
Han, S., Lin, F., Qi, Y., Liu, C., Zhou, L., Xia, Y., Chen, K., Ji, X., Li, H., Yu, W., et al. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/3846217 · Cited by 99 · see citing works
“The kidney performs an important role in the metabolism and homeostasis of iron, and iron metabolism disorders are also closely implicated in the development and progression of many tumors [10, 11].”
Magnetic nanoparticles for ferroptosis cancer therapy with diagnostic imaging
Ko, M. J., Min, S., Hong, H., Yoo, W., Joo, J., Zhang, Y. S., Kang, H., & Kim, D. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.09.015 · Cited by 99 · see citing works
“Cancer cells are highly sensitive to iron concentration, and a slight fluctuation in iron concentration in the process of intracellular iron homeostasis can cause a great impact on the fate of the cancer cells [144 – 148].”
Nanoenabled Intracellular Metal Ion Homeostasis Regulation for Tumor Therapy
Xu, L., Peng, M., Gao, T., Wang, D., Lian, X., Sun, H., Shi, J., Wang, Y., & Wang, P. (2023) · Advanced Science · doi:10.1002/advs.202306203 · Cited by 98 · see citing works
Electrochemical synthesis of carbon dots with a Stokes shift of 309 nm for sensing of Fe3+ and ascorbic acid
An, Q., Lin, Q., Huang, X., Zhou, R., Guo, X. R., Xu, W., Wang, S., Xu, D., & Chang, H. (2020) · Dyes and Pigments · doi:10.1016/j.dyepig.2020.108878 · Cited by 93 · see citing works
Ferritinophagy, a form of autophagic ferroptosis: New insights into cancer treatment
Sun, K., Li, C., Liao, S., Yao, X., Ouyang, Y., Liu, Y., Wang, Z., Li, Z., & Yao, F. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1043344 · Cited by 95 · see citing works
“Research related to cancer and ferritinophagy conducted over the past few years has shown new intracellular processes and mechanisms connecting iron and cancer (Manz et al., 2016).”
Background
Ferrosenescence: The iron age of neurodegeneration?
Sfera, A., Bullock, K., Price, A. I., Inderias, L., & Osorio, C. P. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.11.012 · Cited by 88 · see citing works
Ferroptosis: Cancer Stem Cells Rely on Iron until “to Die for” It
Cosialls, E., Elhage, R., Santos, L. D., Gong, C., Mehrpour, M., & Hamaï, A. (2021) · Cells · doi:10.3390/cells10112981 · Cited by 90 · see citing works
Antiferroptotic activity of non-oxidative dopamine
Wang, D., Peng, Y., Xie, Y., Zhou, B., Sun, X., Kang, R., & Tang, D. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.10.099 · Cited by 88 · see citing works
Dietary Intakes of Calcium, Iron, Magnesium, and Potassium Elements and the Risk of Colorectal Cancer: a Meta-Analysis
Meng, Y., Sun, J., Yu, J. Q., Wang, C., & Su, J. (2018) · Biological Trace Element Research · doi:10.1007/s12011-018-1474-z · Cited by 87 · see citing works
p53 Promoted Ferroptosis in Ovarian Cancer Cells Treated with Human Serum Incubated-Superparamagnetic Iron Oxides
Zhang, Y., Xia, M., Zhou, Z., Hu, X., Wang, J., Zhang, M., Li, Y., Sun, L., Chen, F., & Yu, H. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s282489 · Cited by 90 · see citing works
Down the Iron Path: Mitochondrial Iron Homeostasis and Beyond
Dietz, J. V., Fox, J. L., & Khalimonchuk, O. (2021) · Cells · doi:10.3390/cells10092198 · Cited by 89 · see citing works
Recent trends in the application of nanoparticles in cancer therapy: The involvement of oxidative stress
Sanati, M., Afshari, A. R., Kesharwani, P., Sukhorukov, V. N., & Sahebkar, A. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.05.035 · Cited by 93 · see citing works
Ferroptosis in lung cancer: a novel pathway regulating cell death and a promising target for drug therapy
Xing, N., Du, Q., Guo, S., Xiang, G., Zhang, Y., Meng, X., Li, X., & Wang, S. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01407-z · Cited by 88 · see citing works
“These cancer cells need more iron during the production process, and the imbalance of iron metabolism can increase the risk of cancer and promote tumor growth [14].”
Background
Mitochondria-mediated Ferroptosis in Diseases Therapy: From Molecular Mechanisms to Implications
Feng, F., He, S., Li, X., He, J., & Luo, L. (2023) · Aging and Disease · doi:10.14336/ad.2023.0717 · Cited by 89 · see citing works
“Tumors, characterized by their active metabolism, high ROS levels, and elevated iron supply, are more susceptible to ferroptosis [153, 154].”
Background
Superparamagnetic Iron Oxide Nanoparticles Modified with Silica Layers as Potential Agents for Lung Cancer Treatment
Reczyńska-Kolman, K., Marszalek, M., Zarzycki, A., Reczyński, W., Kornaus, K., Pamuła, E., & Chrzanowski, W. (2020) · Nanomaterials · doi:10.3390/nano10061076 · Cited by 86 · see citing works
“The prevention of iron release from the SPIONs was of utmost importance, since iron is considered as a cofactor in cancer cell proliferation [23,40].”
Background
Ferroptosis as a novel form of regulated cell death: Implications in the pathogenesis, oncometabolism and treatment of human cancer
Pu, F., Chen, F., Zhang, Z., Shi, D., Zhong, B., Lv, X., Tucker, A. B., Fan, J., Li, A. J., Qin, K. H., et al. (2020) · Genes & Diseases · doi:10.1016/j.gendis.2020.11.019 · Cited by 86 · see citing works
“This outcome suggests that cells with RAS mutations have increased iron intake and reduced iron storage capacity, and the resultant iron overload can induce ferroptosis.(48,49) Studies have shown that the use of iron chelating agents (deferramine) inhibit erastin-induced ferroptosis, and supplementation with exogenous…”
Background
Ultrasmall iron oxide nanoparticles induced ferroptosis via Beclin1/ATG5-dependent autophagy pathway
Wen, J., Chen, H., Ren, Z., Zhang, P., Chen, J., & Jiang, S. (2021) · Nano Convergence · doi:10.1186/s40580-021-00260-z · Cited by 86 · see citing works
Characterization of a ferroptosis and iron-metabolism related lncRNA signature in lung adenocarcinoma
Yao, J., Chen, X., Liu, X., Li, R., Zhou, X., & Qu, Y.-Q. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02027-2 · Cited by 86 · see citing works
Effective ferroptotic small-cell lung cancer cell death from SLC7A11 inhibition by sulforaphane
Iida, Y., Okamoto-Κatsuyama, M., Maruoka, S., Mizumura, K., Shimizu, T., Shikano, S., Hikichi, M., Takahashi, M., Tsuya, K., Okamoto, S., et al. (2020) · Oncology Letters · doi:10.3892/ol.2020.12332 · Cited by 82 · see citing works
“Furthermore, excess iron has been found to contribute to tumor growth (39), and previous studies have reported that cancer cells exhibited increased expression levels of transferrin receptors and iron uptake (40,41).”
Zooming in and out of ferroptosis in human disease
Wang, X., Zhou, Y., Min, J., & Wang, F. (2023) · Frontiers of Medicine · doi:10.1007/s11684-023-0992-z · Cited by 83 · see citing works
Understanding the Political Challenge of Red and Processed Meat Reduction for Healthy and Sustainable Food Systems: A Narrative Review of the Literature
Sievert, K., Lawrence, M. A., Parker, C., & Baker, P. (2020) · International Journal of Health Policy and Management · doi:10.34172/ijhpm.2020.238 · Cited by 86 · see citing works
Novel antitumor compound optimized from natural saponin Albiziabioside A induced caspase-dependent apoptosis and ferroptosis as a p53 activator through the mitochondrial pathway
Wei, G., Sun, J., Hou, Z., Luan, W., Wang, S., Cui, S., Cheng, M., & Liu, Y. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.08.036 · Cited by 81 · see citing works
Links Between Iron and Lipids: Implications in Some Major Human Diseases
Rockfield, S., Chhabra, R., Robertson, M., Rehman, N., Bisht, R., & Nanjundan, M. (2018) · Pharmaceuticals · doi:10.3390/ph11040113 · Cited by 78 · see citing works
“Cancer cells are described to be “addicted” to iron [8]; indeed, their increased proliferative capacity is negatively regulated upon cellular treatment with iron chelators [82].”
Background
High-Dose Vitamin C for Cancer Therapy
Mussa, A., Idris, R. A. M., Ahmed, N., Ahmad, S., Murtadha, A. H., Din, T. A. D. A. T., Yean, C. Y., Rahman, W. F. W. A., Lazim, N. M., Uskoković, V., et al. (2022) · Pharmaceuticals · doi:10.3390/ph15060711 · Cited by 81 · see citing works
“Cell respiration, DNA synthesis, the cell cycle, and epigenetics are all regulated by iron and haem-associated proteins [91,93].”
Background
Immunogenic cell death in cancer immunotherapy
Choi, M., Shin, J., Lee, C.-E., Chung, J.-Y., Kim, M., Yan, X., Yang, W., & Cha, J. (2023) · BMB Reports · doi:10.5483/bmbrep.2023-0024 · Cited by 78 · see citing works
“on iron for cell growth, a new therapeutic approach using ferroptosis for cancers resistant to conventional anticancer drugs has been proposed (75-77).”
Background
Functions and Implications of Autophagy in Colon Cancer
Devenport, S. N., & Shah, Y. M. (2019) · Cells · doi:10.3390/cells8111349 · Cited by 75 · see citing works
“Certain cancers have shown a sensitivity to ferroptosis [64] and pharmacological induction of ferroptosis is found to reduce pancreatic and hepatic cancer cell growth [63,65].”
Background
Flipside of the Coin: Iron Deficiency and Colorectal Cancer
Aksan, A., Farrag, K., Aksan, S., Schroeder, O., & Stein, J. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.635899 · Cited by 74 · see citing works
Energy‐Free, Singlet Oxygen‐Based Chemodynamic Therapy for Selective Tumor Treatment without Dark Toxicity
Chen, Y., Deng, J., Liu, F., Dai, P., An, Y., Wang, Z., & Zhao, Y. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201900366 · Cited by 70 · see citing works
Mitochondrial Iron Metabolism: The Crucial Actors in Diseases
Duan, G., Li, J., Duan, Y., Zheng, C., Guo, Q., Li, F., Zheng, J., Yu, J., Zhang, P., Wan, M., et al. (2022) · Molecules · doi:10.3390/molecules28010029 · Cited by 73 · see citing works
“Iron chelators affect the initiation, growth, proliferation, and metastasis of cancer cells by targeting different stages of disease progression, including associated iron metabolic pathways and iron-containing proteins [160,173].”
Background
A novel ferroptosis-related 12-gene signature predicts clinical prognosis and reveals immune relevancy in clear cell renal cell carcinoma
Hong, Y., Lin, M., Ou, D., Huang, Z., & Shen, P. (2021) · BMC Cancer · doi:10.1186/s12885-021-08559-0 · Cited by 68 · see citing works
“Page 3/15 Iron is an essential element in the basic biological processes of human body, and the metabolism disorder of which is involved with the occurrence and progression of many tumors (5, 6).”
Background
Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy
Lelièvre, P., Sancey, L., Coll, J., Deniaud, A., & Busser, B. (2020) · Cancers · doi:10.3390/cancers12123524 · Cited by 66 · see citing works
“Finally, the regulation of iron homeostasis is also controlled by another mechanism: miRNAs which participate in the silencing of certain RNA and have a direct effect on the post-transcriptional regulation of the genes involved in the regulation of iron metabolism [22,23].”
Background
Friend or Foe? Recent Strategies to Target Myeloid Cells in Cancer
Chaib, M., Chauhan, S., & Makowski, L. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00351 · Cited by 62 · see citing works
Ferroptosis Driver SOCS1 and Suppressor FTH1 Independently Correlate With M1 and M2 Macrophage Infiltration in Head and Neck Squamous Cell Carcinoma
Hu, Z., Wen, Y., Ma, R., Chen, L., Zeng, X., Wen, W., & Sun, W. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.727762 · Cited by 66 · see citing works
PRMT3‐Mediated Arginine Methylation of METTL14 Promotes Malignant Progression and Treatment Resistance in Endometrial Carcinoma
Wang, Y., Wang, C., Guan, X., Ma, Y., Zhang, S., Li, F., Yin, Y., Sun, Z., Chen, X., & Yin, H. (2023) · Advanced Science · doi:10.1002/advs.202303812 · Cited by 65 · see citing works
Appropriate Size of Fe 3 O 4 Nanoparticles for Cancer Therapy by Ferroptosis
Tian, X., Ruan, L., Zhou, S., Wu, L. H., Cao, J., Qi, X., Zhang, X., & Shen, S. (2022) · ACS Applied Bio Materials · doi:10.1021/acsabm.2c00068 · Cited by 65 · see citing works
Targeted Co-delivery of the Iron Chelator Deferoxamine and a HIF1α Inhibitor Impairs Pancreatic Tumor Growth
Lang, J., Zhao, X., Wang, X., Zhao, Y., Li, Y., Zhao, R., Cheng, K., Li, Y., Han, X., Zheng, X., et al. (2019) · ACS Nano · doi:10.1021/acsnano.8b08823 · Cited by 61 · see citing works
Ferroptosis is Involved in Hypoxic-ischemic Brain Damage in Neonatal Rats
Lin, W., Zhang, T., Zheng, J., Zhou, Y., Lin, Z., & Fu, X. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.02.013 · Cited by 64 · see citing works
“Proteins involved in iron metabolism are critical regulators of ferroptosis mechanisms (Manz et al., 2016).”
Prospective role and immunotherapeutic targets of sideroflexin protein family in lung adenocarcinoma: evidence from bioinformatics validation
Dang, H.-H., Ta, H. D. K., Nguyen, T. T. T., Anuraga, G., Wang, C., Lee, K., & Le, N. Q. K. (2022) · Functional & Integrative Genomics · doi:10.1007/s10142-022-00883-3 · Cited by 64 · see citing works
“Cancer cells are avid users of iron, and its accumulation can drive tumor initiation and maintenance (Manz et al. 2016).”
Background

Role of dietary iron revisited: in metabolism, ferroptosis and pathophysiology of cancer.
Pandrangi, S. L., Chittineedi, P., Chikati, R., Lingareddy, J. R., Nagoor, M., & Ponnada, S. K. (2022) · PubMed Central · Cited by 32 · see citing works
Iron metabolism and its contribution to cancer (Review)
Chen, Y., Fan, Z., Yang, Y., & Gu, C. (2019) · International Journal of Oncology · doi:10.3892/ijo.2019.4720 · Cited by 142 · see citing works
Iron in Shaping Cancer Biology
Battaglia, A. M., Costanzo, F. S., & Biamonte, F. (2024) · Springer eBooks · doi:10.1007/978-3-030-80962-1_374-1
The Role of Iron in Cancer Progression
Guo, Q., Li, L., Hou, S., Yuan, Z., Li, C., Zhang, W., Zheng, L., & Li, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.778492 · Cited by 150 · see citing works
Iron and Cancer
Torti, S. V., Manz, D. H., Paul, B. T., Blanchette-Farra, N., & Torti, F. M. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-082117-051732 · Cited by 426 · see citing works
Self-citation

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
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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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