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

  • Cell Death Dis. 2025 Jun 18;16(1):458. doi: 10.1038/s41419-025-07764-0.
Xu Yang  #  1 ,  Long Yu  #  1 ,  Miaomiao Shao  #  2 ,  Huiling Yang  3 ,  Kangwei Qi  1 ,  Gaofei He  1 ,  Lanxin Wang  1 ,  Di Kong  1 ,  Jianxin Gu  1 ,  Xiaolin Xu  4 ,  Lan Wang  5
Affiliations
  • 1. NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • 2. School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
  • 3. Department of Pathology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
  • 4. Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Naval Medical University, Shanghai, 200003, China. [email protected].
  • 5. NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 40533443 DOI: 10.1038/s41419-025-07764-0
Abstract

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 (m6A) 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.

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