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

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.

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.

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.

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.