YTHDC2 inhibits the resistance of lung cancer to EGFR-TKI through cuproptosis.

While third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, have significantly improved patient survival in non-small cell lung cancer (NSCLC), acquired resistance remains a major clinical challenge, and its underlying mechanisms are incompletely understood. In this study, we demonstrate that YTHDC2 expression is significantly downregulated in osimertinib-resistant patient-derived xenograft (PDX) tissues and lung cancer cell lines compared to their osimertinib-sensitive counterparts. Further investigation revealed that YTHDC2 overcomes osimertinib resistance in lung cancer cells by promoting cuproptosis. Mechanistically, YTHDC2 binds to mA-modified sites (specifically at nucleotides A1223 and A2824) within the mRNA of the copper transporter SLC31A1 in an mA-dependent manner. This interaction enhances SLC31A1 mRNA stability and protein expression, thereby increasing intracellular copper transport and inducing cuproptosis in tumor cells. Additionally, we found that the copper ionophore disulfiram (DSF) overcame osimertinib resistance by augmenting YTHDC2 expression. Collectively, our findings elucidate a novel YTHDC2-SLC31A1-cuproptosis axis as a key mechanism underlying EGFR-TKI resistance and propose new therapeutic strategies for its reversal.