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We further demonstrated that phosphatidylethanolamine (PE) levels are elevated during HEV-3ra infection in pregnant rabbits, and that inhibition of PE biosynthesis by CRISPR\/Cas9-mediated knockdown and silencing of phosphatidylserine decarboxylase\/phosphoethanolamine cytidylyltransferase genes that are responsible for PE synthesis resulted in decreased HEV replication, indicating that PE is important for HEV replication. Additionally, we found that placental lactogen hormone, which is elevated during late pregnancy, stimulated fatty acid accumulation and potentiated HEV replication, therefore providing a potential explanation for pregnancy-associated adverse outcomes. Collectively, our findings reveal an important role of host lipid metabolism in HEV replication and offer mechanistic insights into lipid-dependent enhancement of HEV replication and a potential role of lipid reprogramming in HEV pathogenesis. 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