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Review Open Access

Copper homeostasis and cuproptosis in Alzheimer's disease (Review)

  • Authors:
    • Chao Cong
    • He Cong
    • Yuan Yao
    • Yuquan Bai
    • Lianwei Xu
  • View Affiliations / Copyright

    Affiliations: Department of Gynecology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China, Department of General Traditional Chinese Medicine, Nanshan Hospital, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, Guangdong 518052, P.R. China, Department of Gynecology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
    Copyright: © Cong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 172
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    Published online on: August 21, 2025
       https://doi.org/10.3892/ijmm.2025.5613
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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuroinflammation, synaptic dysfunction and neuronal loss. Research has revealed a connection between copper metabolism and the pathophysiology of AD, particularly through a newly identified form of copper‑dependent cell death referred to as cuproptosis. Cuproptosis is driven by the aggregation of lipoylated proteins and proteotoxic stress caused by excessive copper accumulation, leading to cellular demise, which is a key event in AD. While studies on copper levels in the brain in AD remain inconclusive, there is mounting evidence suggesting that an imbalance in copper homeostasis, particularly elevated labile copper levels, contributes to oxidative damage and neurodegeneration in patients with AD. The present review examines the role of cuproptosis in AD and discusses how targeting this pathway may provide novel therapeutic opportunities. By investigating the underlying mechanisms and potential clinical implications, the present review highlights that regulation of cuproptosis provides a promising approach for modulating disease progression and developing personalized treatment strategies for AD.
View Figures

Figure 1

Copper absorption and transport.
Dietary copper is primarily absorbed in the duodenum and proximal
small intestine via the CTR1 transporter, following reduction of
Cu2+ to Cu+ by STEAP and DCYTB. Once
absorbed, copper is either stored in intestinal cells by
metallothioneins or transported to the liver via ATP7A. In the
liver, copper is distributed and stored, with any excess excreted
through bile. This process ensures systemic copper homeostasis and
bioavailability. CP, ceruloplasmin; CTR1, copper transporter 1;
DCYTB, duodenal cytochrome B; HIS, histidine; HSA, human serum
albumin; MG, metal group; MT, metallothionein; STEAP,
six-transmembrane epithelial antigen of the prostate.

Figure 2

Mechanism of cuproptosis in neurons.
Excessive copper [Cu2+] is transported into cells via
elesclomol. The accumulation of Cu2+ disrupts Fe-S
cluster proteins and lipoic acid-dependent enzymes such as DLAT.
Copper-induced stress depletes GSH, an antioxidant that protects
cells from oxidative damage. Additionally, some extracellular
Cu2+ is reduced to Cu+ by metalloreductases
and transported into cells via CTR1. This Cu+ in
mitochondria can directly trigger cuproptosis.
Cu+/Cu2+, reduced/oxidized copper ion; CTR1,
copper transporter 1; DLAT, dihydrolipoamide S-acetyltransferase;
FDX1, ferredoxin 1; Fe-S, iron-sulfur; GSH, glutathione; LA, lipoic
acid; LIAS, lipoic acid synthase; MT, metallothionein.

Figure 3

Copper dyshomeostasis and its dual
impact on AD. Both copper excess and deficiency contribute to AD
pathogenesis. Copper overload induces Aβ aggregation, Tau
phosphorylation, oxidative stress (via the Fenton reaction) and
neuroinflammation with neuronal loss. Conversely, copper deficiency
reduces antioxidant enzymes (such as SOD, CP and LOX) and Cox
activity, leading to impaired mitochondrial function and elevated
ROS levels. These disruptions in copper homeostasis accelerate
neurodegeneration. Aβ, amyloid-β; AD, Alzheimer's disease; CP,
ceruloplasmin; Cox, cyclooxygenase; CTR1, copper transporter 1;
DLAT, dihydrolipoamide S-acetyltransferase; Fe-S, iron-sulfur; LOX,
lysyl oxidase; ROS, reactive oxygen species; SOD, superoxide
dismutase; STEAP, six-transmembrane epithelial antigen of the
prostate.
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Copy and paste a formatted citation
Spandidos Publications style
Cong C, Cong H, Yao Y, Bai Y and Xu L: Copper homeostasis and cuproptosis in Alzheimer's disease (Review). Int J Mol Med 56: 172, 2025.
APA
Cong, C., Cong, H., Yao, Y., Bai, Y., & Xu, L. (2025). Copper homeostasis and cuproptosis in Alzheimer's disease (Review). International Journal of Molecular Medicine, 56, 172. https://doi.org/10.3892/ijmm.2025.5613
MLA
Cong, C., Cong, H., Yao, Y., Bai, Y., Xu, L."Copper homeostasis and cuproptosis in Alzheimer's disease (Review)". International Journal of Molecular Medicine 56.5 (2025): 172.
Chicago
Cong, C., Cong, H., Yao, Y., Bai, Y., Xu, L."Copper homeostasis and cuproptosis in Alzheimer's disease (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 172. https://doi.org/10.3892/ijmm.2025.5613
Copy and paste a formatted citation
x
Spandidos Publications style
Cong C, Cong H, Yao Y, Bai Y and Xu L: Copper homeostasis and cuproptosis in Alzheimer's disease (Review). Int J Mol Med 56: 172, 2025.
APA
Cong, C., Cong, H., Yao, Y., Bai, Y., & Xu, L. (2025). Copper homeostasis and cuproptosis in Alzheimer's disease (Review). International Journal of Molecular Medicine, 56, 172. https://doi.org/10.3892/ijmm.2025.5613
MLA
Cong, C., Cong, H., Yao, Y., Bai, Y., Xu, L."Copper homeostasis and cuproptosis in Alzheimer's disease (Review)". International Journal of Molecular Medicine 56.5 (2025): 172.
Chicago
Cong, C., Cong, H., Yao, Y., Bai, Y., Xu, L."Copper homeostasis and cuproptosis in Alzheimer's disease (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 172. https://doi.org/10.3892/ijmm.2025.5613
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