Zinc transporter 1 functions in copper uptake and cuproptosis

Copper (Cu) is a co-factor for several essential metabolic enzymes. Disruption of Cu homeostasis results in genetic diseases such as Wilson's disease. Here, we show that the zinc transporter 1 (ZnT1), known to export zinc (Zn) out of the cell, also mediates Cu²⁺ entry into cells and is required for Cu²⁺-induced cell death, cuproptosis. Structural analysis and functional characterization indicate that Cu²⁺ and Zn²⁺ share the same primary binding site, allowing Zn²⁺ to compete for Cu²⁺ uptake. Among ZnT members, ZnT1 harbors a unique inter-subunit disulfide bond that stabilizes the outward-open conformations of both protomers to facilitate efficient Cu²⁺ transport. Specific knockout of the ZnT1 gene in the intestinal epithelium caused the loss of Lgr5+ stem cells due to Cu deficiency. ZnT1, therefore, functions as a dual Zn²⁺ and Cu²⁺ transporter and potentially serves as a target for using Zn²⁺ in the treatment of Wilson's disease caused by Cu overload.