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Copper dyshomeostasis and cardiovascular disease: Molecular mechanisms and new strategies for targeted intervention with cuproptosis (Review)

  • Authors:
    • Peiyu Li
    • Yinghui Li
    • Qian Meng
    • Jie Wang
    • Kun Wang
    • Sumin Yang
  • View Affiliations / Copyright

    Affiliations: Key Laboratory of Maternal and Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, Shandong 250014, P.R. China, Department of Cardiovascular Surgery, Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, Shandong 266021, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].
  • Article Number: 19
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    Published online on: November 13, 2025
       https://doi.org/10.3892/ijmm.2025.5690
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Abstract

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide and their pathological mechanisms have remained a major focus of research. Notably, copper has an essential role in maintaining cardiovascular homeostasis and disruption of copper metabolism can lead to a range of pathological consequences. The present review summarizes the dynamic balance of copper metabolism, clarifies its regulatory network encompassing intestinal absorption, intracellular transport, tissue storage and excretion, and emphasizes the molecular associations between copper dyshomeostasis and CVDs, including atherosclerosis and stroke. Notably, cuproptosis, a newly identified mode of regulated cell death, provides novel insights into the role of copper‑induced cell death in the cardiovascular system. Based on current research progress, the current review also discusses the value of therapeutics that target copper metabolism, such as copper chelators, ionophores and dietary interventions. Furthermore, key unanswered questions are identified, particularly those regarding the specific molecular pathways linking copper homeostasis to cardiovascular function.
View Figures

Figure 1

Dietary copper ions are absorbed into
the bloodstream through the small intestinal epithelium, and
transported to the liver and other tissues by binding to soluble
chaperones. The absorption of copper ions is mediated by CTR1,
while its excretion is co-regulated by ATP7A and ATP7B.
Intracellular copper ions can form complexes with GSH and MT for
storage, or be targeted to subcellular structures via specific
chaperones (such as CCS, SOD1, ATOX1 and COX17) to participate in
enzyme assembly. Ultimately, copper ions are excreted from the body
through bile. CTR1, copper transporter 1; ATP7A,
copper-transporting ATPase α; ATP7B, copper-transporting ATPase β;
GSH, glutathione; MT, metallothionein; CCS, copper chaperone for
superoxide dismutase; SOD1, superoxide dismutase 1; ATOX1,
antioxidant 1; COX17/11, COX copper chaperone 17/11; COX,
cytochrome c oxidase; SCO, synthesis of COX.

Figure 2

Copper ionophores, such as
elesclomol, form complexes with extracellular copper ions through
chelation and deliver them to various areas within cells.
Intracellular copper overload causes aggregation of lipoylated
mitochondrial enzymes in the tricarboxylic acid cycle (such as
DLAT) and promotes the loss of Fe-S clusters, thereby causing
proteotoxic stress and cell death. Copper ions also catalyze the
Fenton reaction to generate ROS, induce cell membrane lipid
peroxidation, damage the inner mitochondrial membrane to disrupt
the mitochondrial electron transport chain, and destroy the DNA
double helix structure, thereby triggering cell death. CTR1, copper
transporter 1; DLAT, dihydrolipoamide S-acetyltransferase; FDX1,
ferredoxin 1; LIAS, lipoic acid synthetase; LA, lipoic acid; Fe-S,
iron-sulfur; ROS, reactive oxygen species.
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Copy and paste a formatted citation
Spandidos Publications style
Li P, Li Y, Meng Q, Wang J, Wang K and Yang S: Copper dyshomeostasis and cardiovascular disease: Molecular mechanisms and new strategies for targeted intervention with cuproptosis (Review). Int J Mol Med 57: 19, 2026.
APA
Li, P., Li, Y., Meng, Q., Wang, J., Wang, K., & Yang, S. (2026). Copper dyshomeostasis and cardiovascular disease: Molecular mechanisms and new strategies for targeted intervention with cuproptosis (Review). International Journal of Molecular Medicine, 57, 19. https://doi.org/10.3892/ijmm.2025.5690
MLA
Li, P., Li, Y., Meng, Q., Wang, J., Wang, K., Yang, S."Copper dyshomeostasis and cardiovascular disease: Molecular mechanisms and new strategies for targeted intervention with cuproptosis (Review)". International Journal of Molecular Medicine 57.1 (2026): 19.
Chicago
Li, P., Li, Y., Meng, Q., Wang, J., Wang, K., Yang, S."Copper dyshomeostasis and cardiovascular disease: Molecular mechanisms and new strategies for targeted intervention with cuproptosis (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 19. https://doi.org/10.3892/ijmm.2025.5690
Copy and paste a formatted citation
x
Spandidos Publications style
Li P, Li Y, Meng Q, Wang J, Wang K and Yang S: Copper dyshomeostasis and cardiovascular disease: Molecular mechanisms and new strategies for targeted intervention with cuproptosis (Review). Int J Mol Med 57: 19, 2026.
APA
Li, P., Li, Y., Meng, Q., Wang, J., Wang, K., & Yang, S. (2026). Copper dyshomeostasis and cardiovascular disease: Molecular mechanisms and new strategies for targeted intervention with cuproptosis (Review). International Journal of Molecular Medicine, 57, 19. https://doi.org/10.3892/ijmm.2025.5690
MLA
Li, P., Li, Y., Meng, Q., Wang, J., Wang, K., Yang, S."Copper dyshomeostasis and cardiovascular disease: Molecular mechanisms and new strategies for targeted intervention with cuproptosis (Review)". International Journal of Molecular Medicine 57.1 (2026): 19.
Chicago
Li, P., Li, Y., Meng, Q., Wang, J., Wang, K., Yang, S."Copper dyshomeostasis and cardiovascular disease: Molecular mechanisms and new strategies for targeted intervention with cuproptosis (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 19. https://doi.org/10.3892/ijmm.2025.5690
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