REVIEW article
Front. Cell Death
Sec. Cellular Stress and Survival: Crosslinks, Intersections, and Pathways
Volume 4 - 2025 | doi: 10.3389/fceld.2025.1628470
Copper-induced cell death mechanisms and their role in the tumor microenvironment
Provisionally accepted
- 1Basic Medicine College, Harbin Medical University, Harbin, China
- 2Haerbin Medical University,China, haerbin, China
- 3Oncology, Chifeng City Hospital, china, Chifeng, China
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Copper is an essential cofactor for all organisms. However, it can become toxic if its concentration rises above a specific level. This level is controlled by evolutionary conserved homeostatic mechanisms. Recently, a new type of cell death called cuproptosis has been found. The process represents a copper-dependent, regulated form of cell death that is distinct from all known death mechanisms and relies on mitochondrial respiration. The mechanism of cuproptosis involves the direct binding of copper to lipidated parts in the tricarboxylic acid (TCA) cycle. This results in the abnormal aggregation of lipoylated proteins and the destabilization of iron-sulfur cluster (Fe-S) proteins. These events induce proteotoxic stress, ultimately leading to cell death. Copper-induced cell death is controlled by proteolipid acylation, which is mediated by the mitochondrial iron-sulfur protein FDX1. Copper overload also inhibits the biosynthesis of iron-sulfur (Fe-S) clusters and impairs the activity of Fe-S enzymes. As a result, mitochondrial function is disrupted. Both copper-induced cell death and impaired copper homeostasis arise from the same mechanistic basis. The expression of copper import gene SLC31A1 (CTR1) and export genes ATP7A and ATP7B significantly influences cuproptosis. The tumor suppressor p53 may participate in this process by modulating glycolysis and mitochondrial metabolism. In contrast, glutathione (GSH) reduces copper ion cytotoxicity by binding copper to form a complex. The growth and spread of tumor cells is more dependent on copper than that of normal cells.The copper ionophore elesclomol (ES) kills cancer cells by transporting copper ions into them. This ES-Cu complex not only inhibits cancer cell proliferation but also activates an immune response.Moreover, when ES is combined with αPD-L1, it might increase the effectiveness of cancer treatment. This gives a new idea for treating cancer.
Keywords: cuproptosis, Copper-overload, Tumor Microenvironment, Fdx1, Proteinlipoylation
Received: 14 May 2025; Accepted: 09 Oct 2025.
Copyright: © 2025 Jiao, Wang, Zhu, Liu, Li, Yang, Zhang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
MingHui Zhang, cfzhangminghui@163.com
Lei Zhang, zhanglei@hrbmu.edu.cn
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