2. Academic Validation
  3. The m6A RNA demethylase FTO promotes radioresistance and stemness maintenance of glioma stem cells

The m6A RNA demethylase FTO promotes radioresistance and stemness maintenance of glioma stem cells

  • Cell Signal. 2025 Aug:132:111782. doi: 10.1016/j.cellsig.2025.111782.
Junhao Zhang 1,  Guoxi Li 2,  Runqiu Wu 2,  Lin Shi 3,  Cong Tian 4,  Hongyan Jiang 4,  Hongyu Che 4,  Yongang Jiang 4,  Zhiyong Jin 4,  Rutong Yu 5,  Xuejiao Liu 6,  Xu Zhang 7
Affiliations

Affiliations

  • 1 Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Xinxiang Central Hospital, Xinxiang 453003, Henan, China.
  • 2 Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3 Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of General Surgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 4 Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 5 Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. Electronic address: rtyu@xzhmu.edu.cn.
  • 6 Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. Electronic address: liuxuejiao0923@xzhmu.edu.cn.
  • 7 Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. Electronic address: zhangxu0502@sina.com.
PMID: 40185350 DOI: 10.1016/j.cellsig.2025.111782
Abstract

Glioblastoma (GBM) was the most common and deadliest malignant brain tumor in adults, with a poor prognosis. Effective targeted drugs are still lacking, and the presence of glioblastoma stem cells (GSC) is a major factor contributing to radiotherapy resistance. Screening for targeted drugs that can sensitize GBM to radiotherapy is crucial. FTO is considered an attractive potential target for tumor therapy, as it mediates m6A demethylation to regulate the stability of target genes. In this study, we evaluated the role of FTO inhibition in promoting the sensitivity of GSC cells to radiotherapy through tumor sphere formation assays, cell Apoptosis assays, and in situ GSC tumor models. We preliminarily explored the molecular mechanisms by transcriptome Sequencing and m6A methylation Sequencing to investigate how inhibiting FTO increases radiotherapy sensitivity. The results showed that downregulation of FTO expression or FTO inhibitor FB23-2 combined with radiotherapy significantly inhibited GSC cell proliferation and self-renewal and increased Apoptosis. FB23-2 combined with radiotherapy effectively inhibited intracranial tumor growth in mice and prolonged the survival of tumor-bearing mice. Furthermore, FTO inhibition sustained the increase of γH2AX expression induced by radiotherapy while decreasing RAD51 expression. Importantly, we found that inhibiting FTO could increase m6A methylation modification of VEGFA, thereby downregulating both mRNA and protein expression of VEGFA. Our findings provide a new therapeutic strategy for enhancing GBM radiotherapy sensitivity and lay the theoretical and experimental groundwork for clinical trials targeting FTO.

Keywords

FB23-2; FTO; Glioma stem cell; Radiotherapy resistance; m6A demethylation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-127103
    99.93%, FTO Inhibitor