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

PMCID: PMC12177039

PMID: 40533443

DOI: 10.1038/s41419-025-07764-0

Journal: Cell death & disease

Publication Date: 2025-6-18

Authors: Yang X, Yu L, Shao M, Yang H, Qi K, et al.

Key Points

• GPX2 serves as a critical mediator of EGFR-TKI resistance in NSCLC by modulating cellular redox balance
• Knockdown of GPX2 reduced gefitinib IC50 by approximately 50% in resistant cell lines
• Targeting GPX2 or its mRNA stability could provide a novel approach to overcoming TKI resistance in NSCLC patients

Summary

This study investigates the mechanisms of resistance to EGFR-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), focusing on the role of glutathione peroxidase 2 (GPX2) in drug resistance. The researchers discovered that GPX2 is upregulated in TKI-resistant NSCLC cells, enhancing the cells' ability to manage oxidative stress and maintain cancer stem cell characteristics through Hedgehog signaling pathway activation.

Using a combination of cellular and molecular techniques, the study demonstrated that GPX2 knockdown significantly reduces gefitinib resistance by disrupting glutathione metabolism and ROS scavenging mechanisms. Mechanistically, the researchers found that METTL14-mediated m6A modification reduces GPX2 mRNA stability, providing a potential therapeutic approach to overcome drug resistance. In vivo xenograft models confirmed that GPX2 deletion enhances the effectiveness of TKI treatment, suggesting a promising strategy for improving NSCLC therapeutic outcomes.