Balancing copper: From redox biology to disease and therapy

Copper is an essential transition metal that plays a central role in biological redox chemistry due to its ability to cycle between the Cu(I) and Cu (II) oxidation states. This redox flexibility enables copper to function as a catalytic cofactor in a wide range of enzymes involved in fundamental processes such as cellular respiration, antioxidant defence, connective tissue formation, and neurotransmitter biosynthesis. However, the same redox activity also poses a risk, as unregulated copper catalyse the formation of harmful free radicals. Copper-mediated oxidative stress, in classical terms, is based on the involvement of copper in Fenton-like reactions. However, copper inside the cell is not free; rather, it is primarily controlled as redox-inactive Cu(I) species, coordinated by thiol-rich buffering system and copper chaperones. Dysregulation of copper homeostasis contributes to pathological conditions, including Wilson disease, Menkes disease and neurodegenerative disorders. In this review, we use copper as a model redox-active metal to examine how coordination control, kinetic regulation, and redox buffering govern cellular homeostasis and signalling and how their misregulation leads to disease, redox imbalance, and disruptions in metallostasis. We propose that metal toxicity arises primarily from failures in coordination and redox control rather than simple metal overload, offering new therapeutic perspectives focused on restoring metal-redox homeostasis rather than indiscriminate metal depletion.