SHROOM2 is an actin-binding protein involved in the regulation of cell motility and actin cytoskeleton remodeling. Schistosome eggs can induce granuloma formation, leading to organized immune aggregates around the eggs. This study unexpectedly observed that Shroom2-deficient mice exhibited a significantly higher mortality rate after infection with Schistosoma japonicum compared to wild-type mice. This study aimed to investigate the disease progression in Shroom2 knockout mice after infection with Schistosoma japonicum, revealing the potential role of the Shroom2 gene in the immune response to schistosome infection and granuloma formation around the eggs. It used CRISPR/Cas9 technology to generate Shroom2 knockout (KO) mice. Both C57BL/6 wild-type (WT) and KO mice were infected with Schistosoma japonicum cercariae (30±2 cercariae/mouse) via abdominal skin exposure. The mice were monitored daily, and the number of deaths was recorded. At the fifth and the seventh weeks post-infection, mice were sacrificed for blood routine analysis and liver histopathology with hematoxylin-eosin (HE) staining. KO mice showed a significant increase in mortality during the acute phase of schistosome infection, accompanied by severe liver pathology and abnormal blood parameters. These findings suggest that the Shroom2 gene plays a critical role in regulating the host immune response, and its deficiency may increase susceptibility to pathogens, accelerating disease progression.