铜元素体内代谢机制及其在相关疾病中的作用与治疗潜力

The in vivo metabolic mechanism of copper and its therapeutic potential in related diseases

摘要

文章系统阐述了人体必需微量元素铜的代谢机制（包括摄取、分布、储存、排出及稳态调控），强调其通过铜离子与亚铜态（或Cu⁺）氧化还原转换参与多种生化反应、维持蛋白质结构与功能的作用，以及过量游离铜诱导活性氧产生进而引发细胞损伤的病理基础。重点分析了铜稳态失调与肝脏疾病、神经退行性疾病、心血管疾病、铜相关遗传病变等多种病理状态的关联，并深入探讨了铜在癌症信号通路中促进肿瘤发生、增殖、血管生成及转移的作用，特别是“铜增生”介导的恶性转化机制。进而，综述了以铜螯合剂、铜离子载体、铜基配合物等铜靶向抗癌治疗策略的研究进展与临床应用潜力。最后，文章指出当前铜靶向疗法面临的核心挑战，包括在不同癌症类型和患者群体中的疗效异质性，以及铜信号网络机制尚未完全明确，并展望精准医学应用、药物联合治疗、新型药物研发等未来研究方向，以期为深化铜相关疾病的病理认知及开发新的癌症治疗策略提供重要理论参考。

Abstract

This review systematically elucidates the metabolic mechanisms of essential trace element copper in humans，including absorption，distribution，storage，excretion，and homeostatic regulation. It emphasizes copper's role in participating in various biochemical reactions and maintaining protein structure and function through the redox conversion between cupric ions and cuprous state（or Cu ⁺），as well as the pathological basis by which excessive free copper induces the production of reactive oxygen species and thereby triggers cellular damage. The review emphasizes the association of copper homeostasis dysregulation with multiple diseases，such as liver disorders，neurodegenerative conditions，cardiovascular diseases，and copper-related genetic diseases. It further explores copper's role in cancer biology，particularly its promotion of tumor initiation，proliferation，angiogenesis，and metastasis via signaling pathways，with a focus on the“copper proliferation”-mediated malignant transformation mechanisms. Additionally，recent advances and clinical potential of copper - targeted anticancer strategies，including copper chelators，ionophores，and complexes are discussed. Finally，the article addresses current challenges in copper-targeted therapies，such as therapeutic heterogeneity across different cancer types and patient populations，and the incomplete understanding of copper signaling networks. Future perspectives are provided，highlighting precision medicine approaches，combination therapies，and novel drug development，aiming to deepen the understanding of copper-related pathology and foster the development of innovative cancer treatments.

关键词

铜 / 微量元素 / 铜代谢 / 铜稳态 / 疾病 / 肿瘤治疗

Key words

copper / trace element / copper metabolism / copper homeostasis / disease / cancer therapy

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基金资助

国家自然科学基金(82372829)

国家自然科学基金(82573035)

江苏省自然科学基金(BK20240130)