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Review Open Access

Role of cuproptosis in digestive system tumors (Review)

  • Authors:
    • Li Zhang
    • Yongpeng Cheng
    • Lulu Tang
    • Jiaxing Zhu
    • Biguang Tuo
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China, Department of Hepatobiliary Surgery, Liupanshui Municipal People's Hospital, Liupanshui, Guizhou 553000, P.R. China, Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 56
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    Published online on: January 2, 2026
       https://doi.org/10.3892/ijmm.2026.5727
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Abstract

In cells, copper levels are tightly regulated because copper deficiency leads to Menkes disease, anemia and neurodegeneration, whereas copper overload is associated with Wilson disease, liver injury, neurodegeneration and several cancers. Cuproptosis, a form of regulated cell death, depends on the intracellular accumulation of excessive copper. This process induces mitochondrial dysfunction and cell death by disrupting the stability of mitochondrial lipoylated proteins and iron‑sulfur cluster proteins. The present review aimed to summarize the mechanisms underlying cuproptosis in gastrointestinal cancer, with a focus on the relationship between copper metabolism imbalance and tumor initiation and progression, as well as the potential therapeutic applications of cuproptosis‑associated agents in oncology. The application prospects of cuproptosis in gastrointestinal tumor therapy are broad, offering novel therapeutic options that may improve prognosis in patients and survival outcomes.
View Figures

Figure 1

Copper metabolism. Extracellular
Cu2+ is reduced to Cu+ by the reductase
STEAP. Some Cu+ is transported to the cell through the
transporter CTR1 to bind to CCS and SOD1, and the remaining portion
is transported to the mitochondria, TGN and nucleus. In
mitochondria, Cu+ participates in the respiratory chain
and redox pathway by binding CCO. In the mitochondrial
intermembrane space, COX17 binds and transfers Cu+ to
SCO1 or COX11, which transfers Cu+ to the cytochrome
oxidase subunit. In the nucleus, Cu+ binds to
transcription factors and drives gene expression. In the TGN, the
Cu+-ATPase transporters ATP7A and ATP7B transfer
Cu+ from the cytoplasm to the lumen of the TGN, where
Cu+ activates Cu-dependent enzymes in the secretory
pathway. When the intracellular Cu+ concentration is
high, ATP7A and ATP7B withdraw from the TGN and promote
Cu+ output. ATOX1, antioxidant 1 copper chaperone;
ATP7A, ATPase copper-transporting α; CCO, cytochrome c oxidase;
CCS, copper chaperone superoxide dismutase; COX17, cytochrome c
oxidase copper chaperone protein 17; SCO1, synthetic cytochrome c
oxidase 1; SOD1, superoxide dismutase 1; STEAP, prostate
six-transmembrane epithelial antigen; SLC31A1, solute carrier
family 31 member 1; TGN, trans-Golgi network.

Figure 2

Molecular mechanism of cuproptosis.
Excess Cu2+ is imported into cells via CTR/SLC31A1 and
as well as copper ionophores elesclomol and DSF. Cu2+ is
reduced to Cu+ mainly through FDX1 and STEAP, increasing
the bioactive Cu+ pool. Mitochondrial Cu+
directly binds lipoylated TCA-cycle enzymes, particularly the
pyruvate dehydrogenase complex, inducing aberrant aggregation of
DLAT and other lipoylated proteins. This aggregation disrupts
lipoylation-dependent TCA activity and Ac-CoA production, and is
accompanied by loss of Fe-S clusters, thereby impairing
Fe-S-dependent enzymes and the ETC. These events drive excessive
ROS generation, oxidative stress, mitochondrial dysfunction and
ultimately cuproptosis-related cell death. Copper homeostasis is
counterbalanced by ATP7A/B-mediated copper efflux/redistribution,
while GSH buffering mitigates copper-associated oxidative stress.
FDX1, ferredoxin 1; TCA, tricarboxylic acid cycle; DLAT,
Dihydrolipoamide S-Acyltransferase; ROS, Reactive Oxygen Species;
DSF, Disulfiram; STEAP, Six-Transmembrane epithelial Antigen of the
Prostate; CTR, Copper Transporter; SLC31A1, Solute Carrier Family
31 Member 1; ATP7A/B, ATPase, Cu2+ Transporting, α/β
polypeptide; Ac-CoA, Acetyl-Coenzyme A; ETC, Electron Transport
Chain; GSH, Glutathione; LIAS, Lipoic Acid Synthase.
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Zhang L, Cheng Y, Tang L, Zhu J and Tuo B: Role of cuproptosis in digestive system tumors (Review). Int J Mol Med 57: 56, 2026.
APA
Zhang, L., Cheng, Y., Tang, L., Zhu, J., & Tuo, B. (2026). Role of cuproptosis in digestive system tumors (Review). International Journal of Molecular Medicine, 57, 56. https://doi.org/10.3892/ijmm.2026.5727
MLA
Zhang, L., Cheng, Y., Tang, L., Zhu, J., Tuo, B."Role of cuproptosis in digestive system tumors (Review)". International Journal of Molecular Medicine 57.3 (2026): 56.
Chicago
Zhang, L., Cheng, Y., Tang, L., Zhu, J., Tuo, B."Role of cuproptosis in digestive system tumors (Review)". International Journal of Molecular Medicine 57, no. 3 (2026): 56. https://doi.org/10.3892/ijmm.2026.5727
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang L, Cheng Y, Tang L, Zhu J and Tuo B: Role of cuproptosis in digestive system tumors (Review). Int J Mol Med 57: 56, 2026.
APA
Zhang, L., Cheng, Y., Tang, L., Zhu, J., & Tuo, B. (2026). Role of cuproptosis in digestive system tumors (Review). International Journal of Molecular Medicine, 57, 56. https://doi.org/10.3892/ijmm.2026.5727
MLA
Zhang, L., Cheng, Y., Tang, L., Zhu, J., Tuo, B."Role of cuproptosis in digestive system tumors (Review)". International Journal of Molecular Medicine 57.3 (2026): 56.
Chicago
Zhang, L., Cheng, Y., Tang, L., Zhu, J., Tuo, B."Role of cuproptosis in digestive system tumors (Review)". International Journal of Molecular Medicine 57, no. 3 (2026): 56. https://doi.org/10.3892/ijmm.2026.5727
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