Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m6A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore- elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.
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