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World J Gastrointest Oncol. Sep 15, 2026; 18(9): 123002
Published online Sep 15, 2026. doi: 10.4251/wjgo.123002
Cuproptosis in gastric cancer: Mechanisms and therapeutic opportunities
Yi-Ping Fang, Shu-Ni Liu, Feng-Ping Liu, Jing-Wen Gong, Yi-Fan Zhang, Jun-Hui Lu, Jing-Wei Liu, Qing Wang, Xing Chen
Yi-Ping Fang, Shu-Ni Liu, Feng-Ping Liu, Department of Gastroenterology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Jing-Wen Gong, Faculty of Graduate Studies, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Yi-Fan Zhang, Department of Gastroenterology, Tianjin Medical University, Tianjin 300203, China
Jun-Hui Lu, Jing-Wei Liu, Xing Chen, Department of Gastroenterology, The First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Qing Wang, Faculty of Graduate Studies, Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
Author contributions: Fang YP designed the review, assessed the literature, and drafted the manuscript; Liu SN developed concepts and organized figures; Liu FP, Gong JW, Zhang YF, Lu JH, Liu JW, and Wang Q critically revised the manuscript for intellectual content; Chen X obtained funding and supervised the study; and the final manuscript was approved by all authors.
AI contribution statement: AI tools, specifically ChatGPT 5.5, were used solely for linguistic refinement, formatting assistance, and editorial consistency checking during manuscript revision. No AI tool was involved in study design, literature selection, data generation, data analysis, interpretation of findings, reference verification, or formulation of scientific conclusions. All AI-assisted outputs were critically reviewed, verified, and revised by the authors, who take full responsibility for the accuracy, originality, integrity, and final content of the manuscript.
Supported by Construction and Validation of a Prognostic Risk Scoring Model Related to Cuproptosis-Characteristic Genes in Gastric Cancer, No. SYYYRC-2022002; and Evaluation of the Efficacy and Safety of Different Doses of Saccharomyces boulardii Combined with Dual Regimens for the Eradication of Helicobacter pylori, No. IIT-2025-125.
Conflict-of-interest statement: The authors state that they have no conflicts of interest relevant to this manuscript.
Corresponding author: Xing Chen, MD, Department of Gastroenterology, The First Hospital of Shanxi Medical University, No. 56 Xinjian South Road, Taiyuan 030001, Shanxi Province, China.
chen0419xing@163.com
Received: May 6, 2026
Revised: May 21, 2026
Accepted: June 15, 2026
Published online: September 15, 2026
Processing time: 113 Days and 9.8 Hours
Gastric cancer remains one of the leading causes of cancer-related mortality, especially when disease recurrence, distant metastasis, and treatment resistance compromise long-term survival. Cuproptosis is a mitochondria-associated, copper-dependent mode of cell death that involves copper-induced clustering of lipoylated tricarboxylic acid cycle proteins, subsequent proteotoxic stress, and destabilization of iron-sulfur cluster proteins. This review summarizes the processes governing copper uptake, intracellular transport, buffering, and export, while outlining the molecular machinery that mediates cuproptosis. It further discusses the role of copper-dependent signaling in gastric cancer biology, with emphasis on receptor tyrosine kinase/mitogen-activated protein kinase pathways, the ubiquitin-proteasome system, autophagy, hypoxia signaling, angiogenesis, and the tumor microenvironment. It also addresses emerging therapies, including copper ionophores, copper chelators, and copper-based or copper-modulating nanoplatforms, and discusses biomarkers and actionable nodes, such as ferredoxin 1, amine oxidase copper-containing 1, integrin beta 1, and serpin family E member 1, which may help stratify patients and guide combinations with chemotherapy, targeted therapy, or immunotherapy. Understanding context-dependent mechanisms, therapeutic windows, and toxicity is essential for translating cuproptosis-based treatment strategies for gastric cancer.
Core Tip: Cuproptosis connects copper imbalance with mitochondrial metabolic vulnerability, angiogenesis, immune regulation, and treatment resistance in gastric cancer. This review summarizes copper homeostasis, protein lipoylation, oncogenic signaling, the tumor microenvironment, and copper-modulating therapies. It highlights copper ionophores, chelators, nanomedicine, and biomarkers, including ferredoxin 1, amine oxidase copper-containing 1, integrin beta 1, and serpin family E member 1, for patient stratification and rational combination therapy while emphasizing toxicity and translational challenges.
