CHD4 is a copper sensor linking chromatin remodeling to cuproptosis

  • Free Radic Biol Med. 2026 Sep:253:90-107. doi: 10.1016/j.freeradbiomed.2026.05.314.
Yongjie Wang  1 ,  Runqiu Chi  2 ,  Congcong Zhang  2 ,  Zijie Liu  3 ,  Xiaoting Tian  4 ,  Aying Wang  2 ,  Qi Sun  4 ,  Yayou Miao  4 ,  Jinjing Xia  5 ,  Yi Shi  6 ,  Jiayi Wang  7 ,  Xiao Zhang  8
Affiliations
  • 1. Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
  • 2. Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
  • 3. Yunnan Key Laboratory of Laboratory Medicine, Kunming, 650032, China.
  • 4. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
  • 5. Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. Electronic address: [email protected].
  • 6. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, 200030, China. Electronic address: [email protected].
  • 7. Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. Electronic address: [email protected].
  • 8. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. Electronic address: [email protected].
PMID: 42176908 DOI: 10.1016/j.freeradbiomed.2026.05.314
Abstract

Cuproptosis is a copper-dependent regulated cell death pathway, but its connection to chromatin regulation is poorly understood. Here, we demonstrate that cuproptosis-sensitive tumor cells exhibit an "epigenetically primed" state with elevated chromatin accessibility and active histone marks. Multi-omics analyses reveal extensive chromatin reprogramming, including topologically associating domain (TAD) fusion and global reduction of enhancer-associated loops. We identify the chromatin remodeler CHD4, a core subunit of the NuRD complex, as a direct copper sensor. Copper ions bind to the CXXC domain of CHD4, triggering its ubiquitin-mediated degradation. As a negative regulator, CHD4 loss causes chromatin decompaction and de-represses the transcription factor HSF2, which directly transactivates the key Cuproptosis executor FDX1. Genetic and pharmacological validations confirm the copper-CHD4-HSF2-FDX1 axis as a central regulator of Cuproptosis susceptibility. In patient-derived models, high HSF2/FDX1 expression predicts enhanced response to Cuproptosis inducers. Our work establishes an epigenetic mechanism linking copper sensing to Cuproptosis and nominates the CHD4/HSF2/FDX1 axis as potential biomarkers and therapeutic targets for precision oncology.

Keywords
Cell death; Elesclomol; Neo-loop; TAD fusion; Transcription.
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