Sun ZJ, Wang K, Li JQ, Song LJ, Liang KN, Cao TL, Jiang HZ. Copper homeostasis imbalance and cuproptosis: Emerging targets and strategies for gastrointestinal tumor therapy. World J Clin Oncol 2026; 17(7): 121645 [DOI: 10.5306/wjco.121645]
Corresponding Author of This Article
Hui-Zhong Jiang, PhD, Professor, Researcher, Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 11 North Third Ring Road East, Beijing 100700, China. jianghz93@126.com
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Medicine, Research & Experimental
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review-article
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Sun ZJ, Wang K, Li JQ, Song LJ, Liang KN, Cao TL, Jiang HZ. Copper homeostasis imbalance and cuproptosis: Emerging targets and strategies for gastrointestinal tumor therapy. World J Clin Oncol 2026; 17(7): 121645 [DOI: 10.5306/wjco.121645]
Zi-Jin Sun, Kai Wang, Ting-Lan Cao, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
Jin-Qiao Li, Shandong First Medical University, Jinan 250117, Shandong Province, China
Lin-Jing Song, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, China
Kang-Ni Liang, Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
Hui-Zhong Jiang, Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
Author contributions: Sun ZJ, Wang K, Li JQ, and Song LJ wrote the original draft; Sun ZJ, Liang KN, and Wang K participated in drafting the manuscript and data integration; Cao TL and Jiang HZ contributed to conceptualization; Cao TL provided critical revisions, and performed language polishing and editing of the manuscript; Jiang HZ contributed to supervision, and final reviewing and editing. All authors have read and approved the final version of the manuscript.
AI contribution statement: ChatGPT was used in this study as a supportive tool solely for language polishing, translation assistance, and improving the clarity and readability of the English text. No other AI tools such as Grammarly or DeepL were used. No part of the main manuscript text was generated by AI, and the scientific content, structure, arguments, and conclusions were entirely prepared by the authors. The use of ChatGPT was strictly limited to language refinement and did not involve scientific writing, content generation, data analysis, or statistical analysis. The study design, experimental procedures, data interpretation, and overall conclusions were independently developed and verified by the authors without any participation of AI tools. In addition, no figures, images, graphical elements, or experimental data visualizations included in the manuscript were generated or modified using AI.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Hui-Zhong Jiang, PhD, Professor, Researcher, Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 11 North Third Ring Road East, Beijing 100700, China. jianghz93@126.com
Received: March 30, 2026 Revised: May 12, 2026 Accepted: June 22, 2026 Published online: July 24, 2026 Processing time: 117 Days and 11.5 Hours
Abstract
Gastrointestinal malignancies, including gastric, colorectal, and pancreatic cancers, are characterized by metabolic reprogramming, multidrug resistance, and immunosuppressive microenvironments that limit clinical outcomes. Cuproptosis is a mitochondrial respiration-dependent form of regulated cell death that may target the “cuproplasia” phenotype of gastrointestinal tumors. Mechanistically, ferredoxin 1-mediated reduction of Cu2+ to Cu+ promotes toxic aggregation of lipoylated tricarboxylic acid cycle proteins, including dihydrolipoamide S-acetyltransferase, and destabilizes iron-sulfur clusters. Therapeutic disruption of copper homeostasis may therefore induce irreversible proteotoxic stress by altering the balance between glycolysis and oxidative phosphorylation. This review summarizes mechanisms of copper homeostasis imbalance and cuproptosis in gastrointestinal malignancies and discusses emerging interventions, including synthetic copper ionophores, traditional Chinese medicine phytochemicals, modulation of the dietary copper-gut microbiota axis, and stimuli-responsive nanomedicine. We further highlight nanomedicine-enabled stromal barrier penetration, magnetic resonance imaging/positron emission tomography-guided theranostics, immunogenic cell death-mediated synergy with immunotherapy, and translational challenges involving ferredoxin 1-based patient stratification and safety window management.
Core Tip: Gastrointestinal malignancies exhibit profound metabolic reprogramming and “cuproplasia”, heavily relying on copper homeostasis for progression and drug resistance. Targeting cuproptosis - a ferredoxin 1-mediated cell death causing toxic aggregation of lipoylated proteins like dihydrolipoamide S-acetyltransferase - offers a transformative strategy to bypass conventional therapeutic resistance. This review highlights multifaceted interventions, including repurposing synthetic copper ionophores, leveraging traditional Chinese medicine phytochemicals, and modulating the unique “dietary copper-gut microbiota” axis. Furthermore, deploying stimuli-responsive nanomedicines helps overcome dense stromal barriers and induces immunogenic cell death, synergizing with immunotherapy to advance the precision management of refractory gastrointestinal tumors.
