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Background <p>Oncolytic virus therapy is a highly promising approach for the treatment of glioblastoma (GBM). The RNA alteration N6-methyladenosine (m<sup>6</sup>A) is essential in GBM progression; however its specific function in oncolytic virotherapy remains unclear.</p> Methods <p>We employed a new oncolytic herpes simplex virus type 1 (HSV-1), designated oHSV-1, which we had previously engineered. Mechanistic studies were performed to elucidate the involved pathways.</p> Results <p>We demonstrate that oHSV-1 specifically downregulates the m<sup>6</sup>A demethylase ALKBH5, leading to GBM cell death. Mechanistically, ALKBH5 downregulation elevates m<sup>6</sup>A modification on the transcript of the arginine methyltransferase CARM1, which promotes mRNA degradation and reduces protein expression. As CARM1 is a vital regulator of apoptosis, its loss triggers tumor cell apoptosis. Thus, our study identifies the ALKBH5–m<sup>6</sup>A–CARM1 axis as a critical mechanism underlying oHSV-1-induced apoptosis in GBM cells. Moreover, the combination of oHSV-1 and CARM1 inhibitor shows a markedly enhanced effect on suppressing tumor cell proliferation in vitro.</p> Conclusions <p>These findings reveal a novel epigenetic mechanism of oHSV-1-induced apoptosis and support the therapeutic potential of combining oHSV-1 with epigenetic inhibitors for GBM treatment.</p>

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oHSV-1-modulated m6A methylation reprogramming through ALKBH5-mediated suppression of CARM1 induced apoptosis in glioblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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  • Xiaoyang Qin,
  • Yan Jia,
  • Peiwen Wang,
  • Hongwei Yang,
  • Rui Wu,
  • Fusheng Liu,
  • Junwen Zhang

摘要

Background

Oncolytic virus therapy is a highly promising approach for the treatment of glioblastoma (GBM). The RNA alteration N6-methyladenosine (m6A) is essential in GBM progression; however its specific function in oncolytic virotherapy remains unclear.

Methods

We employed a new oncolytic herpes simplex virus type 1 (HSV-1), designated oHSV-1, which we had previously engineered. Mechanistic studies were performed to elucidate the involved pathways.

Results

We demonstrate that oHSV-1 specifically downregulates the m6A demethylase ALKBH5, leading to GBM cell death. Mechanistically, ALKBH5 downregulation elevates m6A modification on the transcript of the arginine methyltransferase CARM1, which promotes mRNA degradation and reduces protein expression. As CARM1 is a vital regulator of apoptosis, its loss triggers tumor cell apoptosis. Thus, our study identifies the ALKBH5–m6A–CARM1 axis as a critical mechanism underlying oHSV-1-induced apoptosis in GBM cells. Moreover, the combination of oHSV-1 and CARM1 inhibitor shows a markedly enhanced effect on suppressing tumor cell proliferation in vitro.

Conclusions

These findings reveal a novel epigenetic mechanism of oHSV-1-induced apoptosis and support the therapeutic potential of combining oHSV-1 with epigenetic inhibitors for GBM treatment.