Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis in endemic regions of Asia.The neurotropism of JEV and its high-efficiency replication in neurons are the key events for pathogenesis.Revealing the interplay between virus and host cells in metabolic facet is of great importance both for unraveling the pathogenesis mechanisms and providing novel antiviral targets.This study took advantage of the integration analysis of metabolomics and transcrip-tomics to depict the metabolic profiles of neurons during the early stage of JEV infection.Increased glycolysis and its branched pentose phosphate pathway (PPP) flux and impaired oxidative phosphorylation (OXPHOS) in glucose utilization,and the catabolic patterns of lipid metabolism were created to facilitate the biosynthesis of precursors needed for JEV replication in neurons.Pharmacological inhibitions of both glycolysis pathway and PPP in neurons suggested its indis-pensable role in maintaining the optimal propagation of JEV.In addition,analysis of metabolomic-transcriptomic regu-latory network showed the pivotal biological function of lipid metabolism during JEV infection.Several pro-inflammatory lipid metabolites were significantly up-regulated and might partially be responsible for the progression of encephalitis.These unique metabolic reprogramming features might give deeper insight into JEV infected neurons and provide promising antiviral approaches targeting metabolism.