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. 2025 Jun 9;43(6):1076-1092.e5.
doi: 10.1016/j.ccell.2025.03.031. Epub 2025 Apr 10.

Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance

Guang Lei  1 , Mingchuang Sun  1 , Jun Cheng  1 , Rui Ye  2 , Zhengze Lu  1 , Amber Horbath  1 , David Huo  1 , Shengrong Wu  1 , Anagha Alapati  1 , Sadhna Aggarwal  2 , Zhihao Xu  1 , Chao Mao  1 , Yuelong Yan  1 , Jun Yao  3 , Qidong Li  1 , Xiong Chen  1 , Hyemin Lee  1 , Li Zhuang  1 , Dadi Jiang  2 , Apar Pataer  4 , Jack A Roth  4 , Nicholas Navin  5 , Albert C Koong  2 , Mingjian James You  6 , Steven H Lin  7 , Boyi Gan  8
Affiliations

Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance

Guang Lei et al. Cancer Cell. .

Abstract

Cuproptosis is a recently identified form of copper-dependent cell death. Here, we reveal that radiotherapy (RT) induces cuproptosis in cancer cells, independent of apoptosis and ferroptosis, and depletes lipoylated proteins and iron-sulfur (Fe-S) cluster proteins-both hallmarks of cuproptosis-in patient tumors. Mechanistically, RT elevates mitochondrial copper levels by upregulating copper transporter 1 (CTR1) and depleting mitochondrial glutathione, a copper chelator, thereby triggering cuproptosis. Integrated analyses of RNA sequencing (RNA-seq) from radioresistant esophageal cancer cells and single-cell RNA-seq from esophageal tumors of patients unresponsive to RT link radioresistance to the downregulation of BTB and CNC homology 1 (BACH1). This downregulation de-represses the expression of copper-sequestering metallothionein (MT) 1E/X, thereby mitigating cuproptosis and contributing to radioresistance. Copper ionophore treatment sensitizes radioresistant cancer cells and cell line- and patient-derived xenografts to RT by potentiating cuproptosis. Our findings unveil a link between RT and cuproptosis and inform a therapeutic strategy to overcome tumor radioresistance by targeting cuproptosis.

Keywords: copper; cuproptosis; metallothionein; radioresistance; radiotherapy.

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Conflict of interest statement

Declaration of interests B.G., G.L., and J.C. have filed a patent for the use of cuproptosis inducers to overcome radioresistance in cancer treatment.

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