GEOGenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE293855GEOGSEfalseAlphavirus M1 disrupts super-enhancer-driven oncogenic transcription in osteosarcoma [ChIP-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.2026/05/31GSE293855GSM8891954GSM8891953GSM8891952GSM8891951GSM8891958GSM8891957GSM8891956GSM889195524676293855Homo sapiens