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作者

Jie Zhang Chengying Lei Guangzhe Zheng Bingxue Nie Yiju Wei Yanqin Lu Shuping Zhang

作者单位

⁴These authors contributed equally ⁵Lead contact ³Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China ¹Department of Respiratory, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China ²Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China

刊名

iScience

年份

2026

卷号

Vol.29 No.4

页码

115438

ISSN

2589-0042

摘要

The FDA-approved disulfiram is metabolized to diethyldithiocarbamate-copper in vivo, exhibiting excellent anti-tumor activity in various types of tumors. Although cuproptosis and ferroptosis are both reported to be involved in the tumor-killing effects of CuET, the specific crosstalk mechanism remains poorly understood. Herein, we found that CuET increased the concentration of copper ions significantly in non-small cell lung cancer cells, thereby triggering the process of cuproptosis. Simulta...更多

The FDA-approved disulfiram is metabolized to diethyldithiocarbamate-copper in vivo, exhibiting excellent anti-tumor activity in various types of tumors. Although cuproptosis and ferroptosis are both reported to be involved in the tumor-killing effects of CuET, the specific crosstalk mechanism remains poorly understood. Herein, we found that CuET increased the concentration of copper ions significantly in non-small cell lung cancer cells, thereby triggering the process of cuproptosis. Simultaneously, we observed an increase in lipid peroxidation and ferroptosis. Mechanistically, CuET interacts directly with polyunsaturated phospholipids to generate free radicals, leading to LPO and ferroptosis, with limited dependence on iron accumulation. Additionally, lipid composition changes induced by CuET might also contribute to ferroptosis. In vivo anti-tumor experiments verified copper-mediated cell death. We uncovered that CuET induced ferroptosis through a copper-triggered, non-canonical, and radical-dependent pathway. Therefore, our data elucidate a therapeutic approach for NSCLC by co-targeting cuproptosis and ferroptosis.收起

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