CUPROPTOSIS: A REVIEW ON MECHANISMS, ROLE IN SOLID AND HEMATOLOGICAL TUMORS, AND ASSOCIATION WITH VIRAL INFECTIONS
Main Article Content
Keywords
Cuproptosis, Solid Tumors, Lymphoma
Abstract
Cuproptosis is a distinct modality of regulated cell death precipitated by an overload of intracellular copper, critically dependent on mitochondrial respiration. The underlying mechanism involves the direct interaction of copper ions with lipoylated components integral to the mitochondrial tricarboxylic acid (TCA) cycle. This binding event triggers the aggregation of these proteins, induces significant proteotoxic stress, and leads to the depletion of essential iron-sulfur cluster proteins, culminating in cell demise. Given that copper homeostasis is frequently dysregulated within cancer cells, rendering them potentially more susceptible to copper-induced toxicity, cuproptosis has rapidly become a focal point of oncological research. This systematic review meticulously analyzes and synthesizes findings from a curated collection of 45 research articles. It aims to provide a comprehensive description of the molecular intricacies of cuproptosis, explore its documented associations with a spectrum of solid tumors (including gastric, lung, liver, neuroblastoma, and ovarian cancers) and lymphoma, and examine its emerging connections with viral infections like COVID-19 and pseudorabies virus. The review elaborates on the reported prognostic significance of cuproptosis-related genes and associated pathways across various malignancies. Furthermore, it details the burgeoning therapeutic strategies designed to harness cuproptosis, encompassing the application of copper ionophores, the development of sophisticated nanomedicine platforms, and synergistic approaches that combine cuproptosis induction with immunotherapy, chemotherapy, or sonodynamic therapy. The potential clinical utility of cuproptosis-associated biomarkers for predicting patient prognosis and therapeutic response is discussed based on the evidence presented in the reviewed literature.
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References
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3. Chen, L., Min, J., & Wang, F. (2022). Copper homeostasis and cuproptosis in health and disease. Signal Transduction and Targeted Therapy, 7, 378. https://doi.org/10.1038/s41392-022-01229-y
4. Ramos, D., Mar, D., Ishida, M., Vargas, R., Gaite, M., Montgomery, A., & Linder, M. C. (2016). Mechanism of Copper Uptake from Blood Plasma Ceruloplasmin by Mammalian Cells. PloS one, 11(3), e0149516. https://doi.org/10.1371/journal.pone.0149516
5. Festa, R. A., & Thiele, D. J. (2011). Copper: an essential metal in biology. Current biology : CB, 21(21), R877–R883. https://doi.org/10.1016/j.cub.2011.09.040
6. Svetlana Lutsenko, Copper trafficking to the secretory pathway, Metallomics, Volume 8, Issue 9, September 2016, Pages 840–852, https://doi.org/10.1039/c6mt00176a
7. Liang, Z. D., Tsai, W. B., Lee, M. Y., Savaraj, N., & Kuo, M. T. (2012). Specificity protein 1 (sp1) oscillation is involved in copper homeostasis maintenance by regulating human high-affinity copper transporter 1 expression. Molecular pharmacology, 81(3), 455–464. https://doi.org/10.1124/mol.111.076422
8. Boyd, S. D., Ullrich, M. S., Skopp, A., & Winkler, D. D. (2020). Copper Sources for Sod1 Activation. Antioxidants (Basel, Switzerland), 9(6), 500. https://doi.org/10.3390/antiox9060500
9. La Fontaine, S., Ackland, M. L., & Mercer, J. F. (2010). Mammalian copper-transporting P-type ATPases, ATP7A and ATP7B: emerging roles. The international journal of biochemistry & cell biology, 42(2), 206–209. https://doi.org/10.1016/j.biocel.2009.11.007
10. Prohaska J. R. (2008). Role of copper transporters in copper homeostasis. The American journal of clinical nutrition, 88(3), 826S–9S. https://doi.org/10.1093/ajcn/88.3.826S
11. Lutsenko, S., Bhattacharjee, A., & Hubbard, A. L. (2010). Copper handling machinery of the brain. Metallomics : integrated biometal science, 2(9), 596–608. https://doi.org/10.1039/c0mt00006j
12. Maung, M. T., Carlson, A., Olea-Flores, M., Elkhadragy, L., Schachtschneider, K. M., Navarro-Tito, N., & Padilla-Benavides, T. (2021). The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 35(9), e21810. https://doi.org/10.1096/fj.202100273RR
13. Wang Y, Yin F, Jin Q, Liu C, Qi Z, Chen D, Luo Y. Cuproptosis: Mechanism and Application in Lymphoma. Curr Cancer Drug Targets. 2024 Jul 11. doi: 10.2174/0115680096296742240614100116. Epub ahead of print. PMID: 38994618.
14. Liu Y, Shen M, Zhu S, Du Z, Lin L, Ma J, Reiter RJ, Ashrafizadeh M, Li G, Zou R, Su H, Ren J, Lu Q. Metallothionein rescues doxorubicin cardiomyopathy via mitigation of cuproptosis. Life Sci. 2025 Feb 15;363:123379. doi: 10.1016/j.lfs.2025.123379. Epub 2025 Jan 8. PMID: 39793852.
15. Cao S, Zhang L, Zhou M, Zhu S. Transcriptomic insights into pseudorabies virus suppressed cell death pathways in neuroblastoma cells. Front Microbiol. 2024 Sep 19;15:1430396. doi: 10.3389/fmicb.2024.1430396. PMID: 39364165; PMCID: PMC11447949.
16. Wang X, Shi Y, Shi H, Liu X, Liao A, Liu Z, Orlowski RZ, Zhang R, Wang H. MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis. J Exp Clin Cancer Res. 2024 Mar 5;43(1):68. doi: 10.1186/s13046-024-02972-6. PMID: 38439082; PMCID: PMC10913264.
17. Xie J, Shao Z, Li C, Zeng C, Xu B. Cuproptosis-related gene ATOX1 promotes MAPK signaling and diffuse large B-cell lymphoma proliferation via modulating copper transport. Biomol Biomed. 2024 Dec 11;25(1):16-28. doi: 10.17305/bb.2024.10536. PMID: 39036924; PMCID: PMC11647247.
18. Sun L, Shao W, Lin Z, Lin J, Zhao F, Yu J. Single-cell RNA sequencing explored potential therapeutic targets by revealing the tumor microenvironment of neuroblastoma and its expression in cell death. Discov Oncol. 2024 Sep 5;15(1):409. doi: 10.1007/s12672-024-01286-5. PMID: 39235657; PMCID: PMC11377405.
19. Yang Z, Su W, Wei X, Pan Y, Xing M, Niu L, Feng B, Kong W, Ren X, Huang F, Zhou J, Zhao W, Qiu Y, Liao T, Chen Q, Qu S, Wang Y, Guan Q, Li D, Zen K, Chen Y, Qin C, Wang Y, Zhou X, Xiang J, Yao B. Hypoxia inducible factor-1α drives cancer resistance to cuproptosis. Cancer Cell. 2025 Mar 6:S1535-6108(25)00067-4. doi: 10.1016/j.ccell.2025.02.015. Epub ahead of print. PMID: 40054467.
20. Chen TH, Lin SH, Lee MY, Wang HC, Tsai KF, Chou CK. Mitochondrial alterations and signatures in hepatocellular carcinoma. Cancer Metastasis Rev. 2025 Feb 18;44(1):34. doi: 10.1007/s10555-025-10251-9. PMID: 39966277; PMCID: PMC11836208.
21. Lyu G, Dai L, Deng X, Liu X, Guo Y, Zhang Y, Wang X, Huang Y, Wu S, Guo JC, Liu Y. Integrative Analysis of Cuproptosis-Related Mitochondrial Depolarisation Genes for Prognostic Prediction in Non-Small Cell Lung Cancer. J Cell Mol Med. 2025 Feb;29(4):e70438. doi: 10.1111/jcmm.70438. PMID: 40008552; PMCID: PMC11862892.
22. Gan Y, Liu T, Feng W, Wang L, Li LI, Ning Y. Drug repositioning of disulfiram induces endometrioid epithelial ovarian cancer cell death via the both apoptosis and cuproptosis pathways. Oncol Res. 2023 May 24;31(3):333-343. doi: 10.32604/or.2023.028694. PMID: 37305383; PMCID: PMC10229305.
23. Chen Y, Liu J, Jia Y, Yang J, Jin Y, Liu Y, Zhong B, Zhao Q. Cell death pathway regulation by fatty acid metabolism-related genes in neuroblastoma: a multi-omics analysis identifying CHD5 as a novel biomarker. Discov Oncol. 2025 Mar 23;16(1):377. doi: 10.1007/s12672-025-02088-z. PMID: 40121577; PMCID: PMC11930905.
24. Masnikosa R, Cvetković Z, Pirić D. Tumor Biology Hides Novel Therapeutic Approaches to Diffuse Large B-Cell Lymphoma: A Narrative Review. Int J Mol Sci. 2024 Oct 23;25(21):11384. doi: 10.3390/ijms252111384. PMID: 39518937; PMCID: PMC11545713.
25. Luo Y, Wang Y, Liu B, Liu Y, Zhang W, Chen S, Rong X, Xu L, Du Q, Liu J, Xu J, Ran H, Wang Z, Guo D. A "CPApoptosis" nano-actuator switches immune-off solid tumors to immune-on for fueling T-cell- based immunotherapy. Theranostics. 2025 Mar 3;15(9):3797-3820. doi: 10.7150/thno.105867. PMID: 40213664; PMCID: PMC11980655.
26. Liu H. Pan-cancer profiles of the cuproptosis gene set. Am J Cancer Res. 2022 Aug 15;12(8):4074-4081. PMID: 36119826; PMCID: PMC9442004.
27. Tang J, Yang J, Yin LK. Prognostic value of disulfidptosis-associated genes in gastric cancer: a comprehensive analysis. Front Oncol. 2025 Mar 4;15:1512394. doi: 10.3389/fonc.2025.1512394. PMID: 40104507; PMCID: PMC11913695.
28. Yan JN, Guo LH, Zhu DP, Ye GL, Shao YF, Zhou HX. Clinical significance and potential application of cuproptosis-related genes in gastric cancer. World J Gastrointest Oncol. 2023 Jul 15;15(7):1200-1214. doi: 10.4251/wjgo.v15.i7.1200. PMID: 37546553; PMCID: PMC10401470.
29. Liu XS, Liu C, Zeng J, Zeng DB, Chen YJ, Tan F, Gao Y, Liu XY, Zhang Y, Zhang YH, Pei ZJ. Nucleophosmin 1 is a prognostic marker of gastrointestinal cancer and is associated with m6A and cuproptosis. Front Pharmacol. 2022 Sep 14;13:1010879. doi: 10.3389/fphar.2022.1010879. PMID: 36188614; PMCID: PMC9515486.
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Jun 29, 2025
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MARTINI, M. (2025) “CUPROPTOSIS: A REVIEW ON MECHANISMS, ROLE IN SOLID AND HEMATOLOGICAL TUMORS, AND ASSOCIATION WITH VIRAL INFECTIONS”, Mediterranean Journal of Hematology and Infectious Diseases, 17(1), p. e2025052. doi: 10.4084/MJHID.2025.052.
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