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Using <jats:italic>in vitro<\/jats:italic> cell models, we previously found that a bystander effect was a cause for Japanese encephalitis\u2010associated endothelial barrier disruption. Brain astrocytes, which neighbor BBB endothelial cells, play roles in the maintenance of BBB integrity. By extending the scope of relevant studies, a potential mechanism has been shown that the activation of neighboring astrocytes could be a cause of disruption of endothelial barrier integrity during the course of Japanese encephalitis viral (JEV) infection. JEV\u2010infected astrocytes were found to release biologically active molecules that activated ubiquitin proteasome, degraded zonula occludens\u20101 (ZO\u20101) and claudin\u20105, and disrupted endothelial barrier integrity in cultured brain microvascular endothelial cells. JEV infection caused astrocytes to release vascular endothelial growth factor (VEGF), interleukin\u20106 (IL\u20106), and matrix metalloproteinases (MMP\u20102\/MMP\u20109). Our data demonstrated that VEGF and IL\u20106 released by JEV\u2010infected astrocytes were critical for the proteasomal degradation of ZO\u20101 and the accompanying disruption of endothelial barrier integrity through the activation of Janus kinase\u20102 (Jak2)\/signal transducer and activator of transcription\u20103 (STAT3) signaling as well as the induction of ubiquitin\u2013protein ligase E3 component, <jats:italic>n<\/jats:italic>\u2010recognin\u20101 (Ubr 1) in endothelial cells. MMP\u2010induced endothelial barrier disruption was accompanied by MMP\u2010mediated proteolytic degradation of claudin\u20105 and ubiquitin proteasome\u2010mediated degradation of ZO\u20101 via extracellular VEGF release. Collectively, these data suggest that JEV infection could activate astrocytes and cause release of VEGF, IL\u20106, and MMP\u20102\/MMP\u20109, thereby contributing, in a concerted action, to the induction of Japanese encephalitis\u2010associated BBB breakdown. 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