Abstract
Cuproptosis involves accumulation of intracellular copper that triggers mitochondrial lipoylated protein aggregation and destabilization of iron–sulfur cluster proteins, leading to cell death. Pharmacologic induction of cuproptosis has been proposed as a cancer therapy. Here, we find that glioblastoma (GBM) stem cells (GSCs) displayed relative resistance to cuproptosis with circadian variation of intracellular copper levels. CRISPR screening of copper regulators under concurrent treatment with copper ionophore or clock disruption revealed dependency on ATPase copper transporting alpha (ATP7A). Circadian control of copper homeostasis was mediated by the core clock transcription factor, brain and muscle ARNT-like 1 (BMAL1). In turn, ATP7A promoted tumor cell growth through regulation of fatty acid desaturation. Copper levels negatively fed back into the circadian circuitry through sequestosome 1/p62–mediated lysosomal degradation of BMAL1. Targeting the circadian clock or fatty acid desaturation augmented cuproptosis antitumor effects. Crosstalk between the core circadian clock and copper sustains GSCs, reshaping fatty acid metabolism and promoting drug resistance, which may inform development of combination therapies for GBM.
Authors
Fanen Yuan, Xujia Wu, Huairui Yuan, Donghai Wang, Tengfei Huang, Po Zhang, Hailong Mi, Weichi Wu, Suchet Taori, Priscilla Chan, Kenji Miki, Maged T. Ghoche, Linjie Zhao, Kalil G. Abdullah, Steve A. Kay, Qiulian Wu, Jeremy N. Rich
Graphical abstract
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)