Copper ion-induced MYH9 polymerization executes cuproptosis.

Cuproptosis is a recently identified form of copper-dependent cell death implicated in various physiological and pathological processes. However, the executive proteins involved and the role of physiological intracellular copper in cuproptosis remain unclear. Herein, we identified myosin heavy-chain 9 (MYH9) as a cuproptosis executioner. Copper binding induced MYH9 polymerization, which disrupted the actin cytoskeleton and led to cuproptotic cell death. Hexyl 2-(3,4,5-trihydroxy-phenyl) acetate (HThPA) was shown to induce cuproptosis by binding to the nuclear receptor Nur77, leading to depletion of copper chelate glutathione (GSH) and release of free copper from intracellular copper stores. Acetylation of MYH9 by acetyltransferase dihydrolipoamide S-acetyltransferase (DLAT) facilitated copper binding, regardless of its extracellular or intracellular origin. Physiological copper levels were higher in drug-resistant tumor cells and clinical samples, which increased the likelihood of HThPA-induced cuproptosis. These results elucidate the mechanisms underlying cuproptosis, establish MYH9 as an executioner, and propose a treatment strategy for drug-resistant tumors.