《生命科学》 2024, 36(8): 1000-1011

铜稳态、铜死亡与铜相关抗肿瘤药物研究进展

孔文哲 , 路　璐 , 樊赛军^*

中国医学科学院北京协和医学院放射医学研究所，天津市放射医学与分子核医学重点实验室，天津 300192

摘　要：

铜是人体必需的微量元素，作为体内众多蛋白质和酶的辅因子，铜参与多种生理活动，铜过载与铜缺乏可导致多种疾病，铜在肿瘤的稳态调节与肿瘤进展中也发挥了重要作用。铜在体内受到铜相关蛋白网络调节，包括铜酶、铜伴侣蛋白和膜转运蛋白等，这些蛋白质共同调节铜的摄入、排出和细胞内利用，从而维持机体铜稳态。铜死亡是一种由线粒体内过量铜离子诱发，靶向三羧酸循环的细胞死亡形式，以线粒体硫辛酰化蛋白聚集和铁硫簇蛋白丢失为特征，铜死亡的发现为包括肿瘤在内的疾病治疗提供了新的研究方向。靶向铜是目前肿瘤研究的方向之一，包括使用铜离子载体提高细胞内铜含量来诱导氧化应激与铜死亡，或使用铜离子螯合剂降低铜的生物利用度。本文综述了铜稳态、铜死亡以及铜相关抗肿瘤药物的最新研究进展，以期为以铜死亡为靶点的肿瘤治疗提供参考。

通讯作者：樊赛军 , Email:fansaijun@irm-cams.ac.cn

Progress in copper homeostasis, cuproptosis, and copper-related antitumor drugs

KONG Wen-Zhe , LU Lu , FAN Sai-Jun^*

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China

Abstract:

Copper is an essential trace metal element for human body. As a cofactor for numerous proteins and enzymes in the organism, copper is involved in a variety of physiological activities. Copper also plays an important role in the regulation of tumor homeostasis and progression. Copper overload and copper deficiency can lead to many diseases, such as Menke’s disease and Wilson’s disease. Thus, copper is regulated by a network of copperrelated proteins, including copper enzymes, copper chaperonins, and membrane transport proteins. These proteins maintain copper homeostasis by regulating copper intake, export and intracellular utilization. Cuproptosis is a novel form of cell death induced by excessive copper ions in the mitochondria. It is characterized by the accumulation of mitochondrial lipoacylated proteins and the loss of iron-sulfur cluster proteins. The discovery of cuproptosis provides a new method for the treatment of diseases, including tumours. Targeting copper is one of the current hotspots in tumor research, including the use of copper ionophores to increase intracellular copper content to induce oxidative stress and cuproptosis, and the use of copper ion chelators to reduce the bioavailability of copper. In this paper, we conducted a systematic review on copper homeostasis, cuproptosis and copper-related antitumor drugs, in order to provide reference for the study of cancer treatment by targeting cuproptosis.

Communication Author：FAN Sai-Jun , Email:fansaijun@irm-cams.ac.cn