Ma Qiang, Gao Shanshan, Li Chaoyang, Yao Junjie, Xie Yumeng, Jiang Cong, Yuan Jie, Fei Ke, Zhang Peng, Wang Hui, Li Xiaoguang
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, P. R. China.
State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
Small. 2025 Feb;21(5):e2406942. doi: 10.1002/smll.202406942. Epub 2024 Dec 15.
Cuproptosis, a newly defined cell death process, represents a novel modality with significant therapeutic potential in cancer treatment. Nevertheless, the modest concentration and transient half-life of copper ions in the bloodstream constrain their efficient delivery into tumor cells. In this study, a copper-based prussian blue nanostructure loaded with serine metabolic inhibitor (NCT-503@Cu-HMPB) is constructed for selectively inducing cuproptosis combined with disrupting serine metabolism. Released within the tumor cells, NCT-503 is found to inhibit cellular serine metabolism and GSH production, ultimately causing metabolic dysfunction, redox imbalance, and increased the formation of Cu that disrupts mitochondrial respiration chain, inducing lipoylated protein dihydrolipoamide S-acetyltransferase (DLAT) aggregation and consequential iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately results in cell death. The findings provide a novel paradigm for tumor therapy based on cuproptosis and metabolic reprogramming, offering prospects for the development of innovative nanotherapeutic platforms in the future.
铜死亡是一种新定义的细胞死亡过程，代表了一种在癌症治疗中具有巨大治疗潜力的新方式。然而，血液中铜离子浓度适中且半衰期短暂，限制了它们有效递送至肿瘤细胞。在本研究中，构建了一种负载丝氨酸代谢抑制剂的铜基普鲁士蓝纳米结构（NCT-503@Cu-HMPB），用于选择性诱导铜死亡并同时破坏丝氨酸代谢。研究发现，释放到肿瘤细胞内的NCT-503可抑制细胞丝氨酸代谢和谷胱甘肽生成，最终导致代谢功能障碍、氧化还原失衡，并增加破坏线粒体呼吸链的铜的形成，诱导脂酰化蛋白二氢硫辛酰胺S-乙酰转移酶（DLAT）聚集以及随之而来的铁硫簇蛋白丢失，从而导致蛋白质毒性应激并最终导致细胞死亡。这些发现为基于铜死亡和代谢重编程的肿瘤治疗提供了一种新的范例，为未来创新纳米治疗平台的开发提供了前景。
