AimsSchistosomiasis is a parasitic disease with a chronic debilitating character caused by parasitic flatworms of the genus Schistosoma. The main disease‐causing species of Schistosoma in China is S. japonicum. M fortis has been proved to be a nonpermissive host of S. japonicum. Mf‐HSP90α (Microtus fortis heat shock protein 90alpha), the homologue of HSP90α, display anti‐schistosome effect in vitro and in vivo. In the current study, in order to investigate the mechanism of anti‐schistosome effect of Mf‐HSP90α, we conducted RNA‐Seq to obtain the transcriptome profile of M. fortis liver infected with S. japonicum at different time points.Methods and ResultsBy mapping the differential expressed genes (DEGs) to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), we found that the JAK2/STAT1 pathway was highly enriched with an elevated level of IL‐10 and HSP90α. We then checked the IL‐10‐JAK2/STAT1‐HSP90α pathway, and found that this pathway was activated in the infected mice with S. japonicum. The expression of the molecules in this pathway was elevated on the 10th day after infection and gradually decreased on the 20th day.ConclusionsThe IL‐10‐JAK2/STAT1‐HSP90α axis was associated with the anti‐schistosome effect of Mf‐HSP90α, and targeting IL‐10‐JAK2/STAT1‐HSP90α axis might be a novel therapeutic strategy for developing resistance to S. japonicum infection.