GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE293nnn/GSE293856/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE293856GEOGSEfalseAlphavirus M1 disrupts super-enhancer-driven oncogenic transcription in osteosarcoma [RNA-seq]Oncolytic virotherapy has shown promise for various cancers, but its application in osteosarcoma (OS) remains underexplored. This study provides the first evidence of the potent oncolytic activity of M1, a natural Getah-like alphavirus, against OS. We demonstrate that OS cells exhibit heightened sensitivity to M1 infection, with its anti-tumor effects not solely dependent on the canonical ER stress-induced apoptosis. Proteomic and ChIP-seq analyses show the DNA-directed RNA polymerase II subunit RPB1 contributes to oncogenic super-enhancer activity and serves as a direct target of M1-mediated regulation. The oncolytic potency correlated positively with the transcriptional dependency on RPB1 within super-enhancer regions. Mechanistically, the viral non-structural protein NSP2 disrupts super-enhancer activity by recruiting the CUL2-RBX1-ELOC complex, which triggers K63-linked ubiquitination and degradation of RPB1. These findings uncover a previously unrecognized oncolytic mechanism of M1 and its therapeutic potential in OS, with RPB1 as a predictive biomarker for virotherapy response.2026/05/31GSE293856GSM8891989GSM8891988GSM8891998GSM8891976GSM8891997GSM8891975GSM8891974GSM8891996GSM8891995GSM8891973GSM8891994GSM8891972GSM8891971GSM8891993GSM8891992GSM8891991GSM8892002GSM8892001GSM8891990GSM8892000GSM8891979GSM8891978GSM8891977GSM8891999GSM8891987GSM8891986GSM8891985GSM8891984GSM8891983GSM8891982GSM8891981GSM889198024676293856Homo sapiens