N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism.

As a predominant oncogenic driver in non-small cell lung cancer (NSCLC), EGFR frequently undergoes amplification or mutation, with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib constituting frontline therapy for advanced EGFR-mutant cases. However, both primary and acquired resistance significantly limit clinical efficacy. Here, we revealed that glutathione metabolic pathway controlled by glutathione peroxidase GPX2 was abnormally activated in gefitinib-resistant A549 and HCC827-GR cell lines. Mechanistically, GPX2 triggers Hedgehog signaling activation through releasing GLI transcriptional regulator, promoting cancer stem cell (CSC) characteristics and TKI resistance. Notably, N6-methyladenosine (m(6)A) modification on GPX2 mRNA mediated by METTL14 diminished its stability. In vivo, GPX2 deletion constrained glutathione metabolism and boosted the effectiveness of TKI in cell line-derived xenograft models. Collectively, these findings demonstrate that GPX2 serves as a positive regulator of both primary and acquired EGFR-TKI resistance and could be a promising therapeutic target for precise treatment of NSCLC.