Review Articles
Vol. 17 No. 1 (2025): Review Articles, Original Article, Scientific Letter, Case Reports Letter to the Editor
CUPROPTOSIS: A REVIEW ON MECHANISMS, ROLE IN SOLID AND HEMATOLOGICAL TUMORS, AND ASSOCIATION WITH VIRAL INFECTIONS
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Received: May 8, 2025
Accepted: June 2, 2025
Accepted: June 2, 2025
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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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Xue Y, Jiang X, Wang J, Zong Y, Yuan Z, Miao S, Mao X. Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma. Biomark Res. 2023 Jan 5;11(1):2. doi: 10.1186/s40364-022-00433-w. PMID: 36600313; PMCID: PMC9814270.
Chen R, Zou J, Kang R, Tang D. The Redox Protein High-Mobility Group Box 1 in Cell Death and Cancer. Antioxid Redox Signal. 2023 Sep;39(7-9):569-590. doi: 10.1089/ars.2023.0236. Epub 2023 Mar 30. PMID: 36999916.
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
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
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
Svetlana Lutsenko, Copper trafficking to the secretory pathway, Metallomics, Volume 8, Issue 9, September 2016, Pages 840–852, https://doi.org/10.1039/c6mt00176a
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
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
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
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
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
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Li J, Wang N, Mao G, Wang J, Xiang M, Zhang H, Zeng D, Ma H, Jiang J. Cuproptosis-associated lncRNA impact prognosis in patients with non-small cell lung cancer co-infected with COVID-19. J Cell Mol Med. 2024 Sep;28(17):e70059. doi: 10.1111/jcmm.70059. PMID: 39228012; PMCID: PMC11371660.
Xu Q, Liu T, Wang J. Radiosensitization-Related Cuproptosis LncRNA Signature in Non-Small Cell Lung Cancer. Genes (Basel). 2022 Nov 9;13(11):2080. doi: 10.3390/genes13112080. PMID: 36360316; PMCID: PMC9690519.
Sun X, Li Z, Meng F, Huang X, Wang J, Song J, Sun L, Zhang P. Cuproptosis associated genes affect prognosis and tumor microenvironment infiltration characterization in lung adenocarcinoma. Am J Cancer Res. 2022 Oct 15;12(10):4545-4565. PMID: 36381320; PMCID: PMC9641400.
Tian XM, Xiang B, Yu YH, Li Q, Zhang ZX, Zhanghuang C, Jin LM, Wang JK, Mi T, Chen ML, Liu F, Wei GH. A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma. Front Immunol. 2022 Sep 23;13:999849. doi: 10.3389/fimmu.2022.999849. PMID: 36211401; PMCID: PMC9540510.
Wang N, Shi S, Li M, Yu X, Ma G. Development and validation of a combined cuproptosis and immunogenic cell death prognostic model for diffuse large B-cell lymphoma. Aging (Albany NY). 2024 Jan 26;16(2):1218-1236. doi: 10.18632/aging.205399. Epub 2024 Jan 26. PMID: 38284893; PMCID: PMC10866411.
Li T, Wang D, Meng M, Yang Z, Luo Z, Li Z, Li F, Liu C, Hao K, Pang X, Tian H, Chen X. Copper-Coordinated Covalent Organic Framework Produced a Robust Fenton-Like Effect Inducing Immunogenic Cell Death of Tumors. Macromol Rapid Commun. 2023 Jun;44(11):e2200929. doi: 10.1002/marc.202200929. Epub 2023 Mar 12. PMID: 36840703.
Chen K, Zhou A, Zhou X, Liu Y, Xu Y, Ning X. An Intelligent Cell-Derived Nanorobot Bridges Synergistic Crosstalk Between Sonodynamic Therapy and Cuproptosis to Promote Cancer Treatment. Nano Lett. 2023 Apr 12;23(7):3038-3047. doi: 10.1021/acs.nanolett.3c00434. Epub 2023 Mar 23. PMID: 36951267.
Li C, Zhang K, Gong Y, Wu Q, Zhang Y, Dong Y, Li D, Wang Z. Based on cuproptosis-related lncRNAs, a novel prognostic signature for colon adenocarcinoma prognosis, immunotherapy, and chemotherapy response. Front Pharmacol. 2023 Jun 12;14:1200054. doi: 10.3389/fphar.2023.1200054. PMID: 37377924; PMCID: PMC10291194.
Cao C, Wang T, Luo Y, Zhang Y, Dai YY, Shen Y. Comprehensive analysis of cuproptosis-associated LncRNAs predictive value and related CeRNA network in acute myeloid leukemia. Heliyon. 2023 Nov 25;9(12):e22532. doi: 10.1016/j.heliyon.2023.e22532. PMID: 38058427; PMCID: PMC10696213.
Tarin M, Babaie M, Eshghi H, Matin MM, Saljooghi AS. Elesclomol, a copper-transporting therapeutic agent targeting mitochondria: from discovery to its novel applications. J Transl Med. 2023 Oct 20;21(1):745. doi: 10.1186/s12967-023-04533-5. PMID: 37864163; PMCID: PMC10589935.
Lu X, Chen X, Lin C, Yi Y, Zhao S, Zhu B, Deng W, Wang X, Xie Z, Rao S, Ni Z, You T, Li L, Huang Y, Xue X, Yu Y, Sun W, Shen X. Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy. Adv Sci (Weinh). 2024 May;11(18):e2309984. doi: 10.1002/advs.202309984. Epub 2024 Mar 2. PMID: 38430531; PMCID: PMC11095170.
Wang S, Liu Y, Su M, Wang Y, Wang W, Wang W, Yang Q, Zhang Z, Hong X, Sun Z, Xiao Y. Near-Infrared Activatable Copper Nanoplatforms Synergize with the 5-Azacytidine Prodrug to Potentiate Cuproptosis. Angew Chem Int Ed Engl. 2024 Dec 20;63(52):e202411609. doi: 10.1002/anie.202411609. Epub 2024 Nov 9. PMID: 39400411.
Zhang N, Yu X, Sun H, Zhao Y, Wu J, Liu G. A prognostic and immunotherapy effectiveness model for pancreatic adenocarcinoma based on cuproptosis-related lncRNAs signature. Medicine (Baltimore). 2023 Oct 20;102(42):e35167. doi: 10.1097/MD.0000000000035167. PMID: 37861553; PMCID: PMC10589590.
Liu J, Chen Z, Deng L, Yao C, Zhou Z, Zhou C, Bin Y, Liu M, Wang L, Wang L, Wang Z. Metal-phenolic networks specifically eliminate hypoxic tumors by instigating oxidative and proteotoxic stresses. Bioact Mater. 2025 Feb 12;47:361-377. doi: 10.1016/j.bioactmat.2025.01.022. PMID: 40026824; PMCID: PMC11870026.
Bai X, Lu F, Li S, Zhao Z, Wang N, Zhao Y, Ma G, Zhang F, Su X, Wang D, Ye J, Li P, Ji C. Cuproptosis-related lncRNA signature as a prognostic tool and therapeutic target in diffuse large B cell lymphoma. Sci Rep. 2024 Jun 5;14(1):12926. doi: 10.1038/s41598-024-63433-w. PMID: 38839842; PMCID: PMC11153514.
Zhang B, Zhang T, Zheng Z, Lin Z, Wang Q, Zheng D, Chen Z, Ma Y. Development and validation of a cuproptosis-associated prognostic model for diffuse large B-cell lymphoma. Front Oncol. 2023 Jan 12;12:1020566. doi: 10.3389/fonc.2022.1020566. PMID: 36713586; PMCID: PMC9877310.
Wang Z, Han M, Wang Y, Wang N, Yang Y, Shao B, Miao Q, Shi Z, Yan F, Feng S. UiO-66 MOFs-Based "Epi-Nano-Sonosensitizer" for Ultrasound-Driven Cascade Immunotherapy against B-Cell Lymphoma. ACS Nano. 2025 Feb 18;19(6):6282-6298. doi: 10.1021/acsnano.4c15761. Epub 2025 Feb 7. PMID: 39920081.
Buccarelli, M., D'Alessandris, Q. G., Matarrese, P., Mollinari, C., Signore, M., Cappannini, A., Martini, M., D'Aliberti, P., De Luca, G., Pedini, F., Boe, A., Biffoni, M., Pallini, R., & Ricci-Vitiani, L. (2021). Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth. Journal of experimental & clinical cancer research : CR, 40(1), 228. https://doi.org/10.1186/s13046-021-02031-4
Luo H, Yan J, Zhang D, Zhou X. Identification of cuproptosis-related molecular subtypes and a novel predictive model of COVID-19 based on machine learning. Front Immunol. 2023 Jul 17;14:1152223. doi: 10.3389/fimmu.2023.1152223. PMID: 37533853; PMCID: PMC10393044.
How to Cite
“CUPROPTOSIS: A REVIEW ON MECHANISMS, ROLE IN SOLID AND HEMATOLOGICAL TUMORS, AND ASSOCIATION WITH VIRAL INFECTIONS” (2025) Mediterranean Journal of Hematology and Infectious Diseases, 17(1), p. e2025052. doi:10.4084/MJHID.2025.052.
Copyright (c) 2025 MAURIZIO MARTINI, Pietro Tralongo, Mariagiovanna Ballato, Vincenzo Fiorentino, Walter Giordano, Valeria zuccalà, Cristina Pizzimenti, Arianna Bakacs, Antonio Ieni, Giovanni Tuccari, Guido Fadda, Luigi Maria Larocca
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