Monkeypox has been spreading worldwide since May 2022, when the World Health Organization (WHO) declared the outbreak of a "Public health emergency of international concern". The spread of monkeypox has posed a serious threat to the health of people all over the world but few studies have been carried out on it, and the molecular mechanism of monkeypox after infection remains unclear. We therefore implemented a transcriptome analysis to identify signaling pathways and biomarkers in monkeypox-infected cells to help understand monkeypox-host cell interactions. In this study, the dataset GSE36854 and GSE11234 were obtained from GEO. Among them, 84 significantly different genes were identified in the dataset GSE36854, followed by KEGG, GO analysis protein-protein interaction (PPI) construction and Hub gene extraction. We also analyzed the expression regulation patterns of hub genes and screened the drugs targeting the hub genes. The results showed that monkeypox-infected cells significantly activated the cellular immune response, and induced inflammatory response. IER3, IFIT2, IL11, ZC3H12A, EREG, IER2, NFKBIE, FST, IFIT1 and AREG were the top 10 hub genes, in which anti-viral gene IFIT1 and IFIT2 were significantly suppressed. AP-26113 and itraconazole promoting the expression of IFIT1 and IFIT2 may be used as new candidates for the treatment of monkeypox viral infection. Our results provide a new entry point for understanding the mode of interaction between monkeypox virus and its host. Keywords: Monkeypox, transcriptome sequencing, protein-protein interaction, IFIT2