Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Natural products as modulators of cuproptosis: A systematic review of mechanisms, therapeutic potential, and future directions.
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Tian Xiaolin, Wei Jun, Liu Guoying, Wang Xi, Li Shuang, Zhang Ximei, Wu Yeke, Hu Jinxia, Wang Shaohui
Аннотация
BACKGROUND: Cuproptosis is a copper ion-dependent form of regulated cell death discovered in 2022. Its mechanism lies in the binding of copper to acylated proteins in the tricarboxylic acid cycle, thereby triggering proteotoxic stress. Natural products, with their structural diversity and good biocompatibility, are gradually becoming regulators of cuproptosis.
PURPOSE: To systematically clarify the mechanisms by which natural products regulate cuproptosis, identify its core targets, and evaluate its therapeutic potential, with a particular focus on cancer therapy and neurodegenerative diseases.
METHODS: Literature from PubMed and CNKI up to August 1, 2026 was retrieved using keywords including "cuproptosis", "copper ionophore", and "natural product", etc.; studies on natural product intervention in cuproptosis in tumors, neurodegenerative diseases, and cardiovascular diseases were screened and included, and the molecular mechanisms, regulatory modes, and therapeutic prospects were comprehensively analyzed.
RESULTS: The core cuproptosis axis involves FDX1-mediated reduction of Cu2+ to Cu+, binding of Cu+ to lipoylated DLAT, and mitochondrial dysfunction. This axis is tightly controlled by copper homeostasis proteins (SLC31A1, ATP7A/B). Natural products bifunctionally modulate cuproptosis. Specifically, they induce tumor cell cuproptosis by elevating intracellular copper or disrupting copper metabolism, and protect normal cells via copper chelation or FDX1 inhibition. Such strategies benefit tumor drug resistance reversal and neuroprotection in neurodegenerative diseases, but their development is restricted by unclear mechanisms, poor druggability and insufficient clinical translation.
CONCLUSION: Natural products are versatile modulators of cuproptosis with dual utility as probes and lead compounds. Future work should identify direct targets, improve druggability, and enable clinical translation.
PURPOSE: To systematically clarify the mechanisms by which natural products regulate cuproptosis, identify its core targets, and evaluate its therapeutic potential, with a particular focus on cancer therapy and neurodegenerative diseases.
METHODS: Literature from PubMed and CNKI up to August 1, 2026 was retrieved using keywords including "cuproptosis", "copper ionophore", and "natural product", etc.; studies on natural product intervention in cuproptosis in tumors, neurodegenerative diseases, and cardiovascular diseases were screened and included, and the molecular mechanisms, regulatory modes, and therapeutic prospects were comprehensively analyzed.
RESULTS: The core cuproptosis axis involves FDX1-mediated reduction of Cu2+ to Cu+, binding of Cu+ to lipoylated DLAT, and mitochondrial dysfunction. This axis is tightly controlled by copper homeostasis proteins (SLC31A1, ATP7A/B). Natural products bifunctionally modulate cuproptosis. Specifically, they induce tumor cell cuproptosis by elevating intracellular copper or disrupting copper metabolism, and protect normal cells via copper chelation or FDX1 inhibition. Such strategies benefit tumor drug resistance reversal and neuroprotection in neurodegenerative diseases, but their development is restricted by unclear mechanisms, poor druggability and insufficient clinical translation.
CONCLUSION: Natural products are versatile modulators of cuproptosis with dual utility as probes and lead compounds. Future work should identify direct targets, improve druggability, and enable clinical translation.