Chemical control of cell adaptation

Cells can adopt distinct states independently of genetic alterations, a biological process commonly referred to as ‘cell-state transition’. Acquisition of distinct cell states is characterized by the upregulation of the plasma membrane glycoprotein CD44 in development, immunity and cancer. Although often described as a cell-surface marker, the molecular function of CD44 has remained elusive for half-a-century. We found that CD44 mediates the uptake of specific metals, including copper and iron using hyaluronate carriers in various tissue types. This glycan-mediated metal endocytosis mechanism enables immune cell activation and acquisition of a drug-tolerant state of cancer cells (cell adaptation). Increase of copper(II) in mitochondria sustains NAD(H) redox cycling, promoting the production of metabolites that co-regulate the epigenetic programming of cell identity. In contrast, increase of iron in the cell nucleus fuels the activity of specific iron- and ketoglutarate-dependent demethylases, enabling specific transcriptional programs. We developed new classes of small molecules that selectively interfere with these metal-catalyzed chemical processes in cells. Inactivating mitochondrial copper(II) prevents acute inflammation in vivo demonstrating that control of cell-state transition confers therapeutic benefits. Pharmacological activation of lysosomal iron, on the other hand, induces ferroptosis in drug-tolerant persister cancer cells, impacting tumor progression. These findings illuminate a universal metal ion uptake mechanism and the critical role of metal ions as regulators of cell adaptation, paving the way towards the development of next generation therapeutics.