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0Recent scientific findings identify myosin heavy-chain 9 (MYH9) as a crucial executive protein that drives cuproptosis, a specialized form of copper-dependent cell death. When cells experience copper overload, the mitochondrial enzyme DLAT translocates to the cytosol and acetylates MYH9, which facilitates copper binding and triggers MYH9 polymerization. This polymerization subsequently collapses the actin cytoskeleton, causing cells to contract into spherical shapes and undergo rapid destruction. While traditional copper ionophores mobilize exogenous copper to induce this pathway, researchers discovered that the small molecule HThPA selectively mobilizes intracellular copper stores. Specifically, HThPA binds the nuclear receptor Nur77 to scaffold a protein complex that activates CHAC1 phosphorylation, thereby depleting glutathione (GSH) and releasing free copper into the cytosol. Because drug-resistant tumor cells inherently maintain elevated intracellular copper levels, they exhibit heightened vulnerability to HThPA-induced cuproptosis. Consequently, targeting this newly mapped intracellular regulatory axis provides a promising therapeutic strategy to overcome treatment resistance in aggressive cancers with minimal adverse side effects.
References:
Wu L, Mi X, Liu Z, et al. Copper ion-induced MYH9 polymerization executes cuproptosis[J]. Cell, 2026.
