CHD4 is a copper sensor linking chromatin remodeling to cuproptosis.

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.