Fig. 4

Schematic of cuproptosis mechanism. Cuproptosis can be triggered by elevating intracellular free copper ion concentration in four ways involved in the absorption, export and storage of copper: (1) treatment with copper ionophores, which shuttle copper into the cell directly, such as ES and DSF; (2) overexpression of SLC31A1, the copper permease specific for reduced copper ion; (3) inhibition of glutathione (GSH) synthesis through BSO, without which free copper ion was released; (4) knockdown of ATP7B, decreasing copper export. Excessive Cu(I) binds to lipoyled DLAT and further leads to DLAT oligomerization, which, together with copper-induced reduction of Fe-S stability or inactivation of Npl4-p97, can lead to the onset of copper-induced cell death. ES elesclomol, DSF disulfiram, BSO L-Buthionine-sulfoximine