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Identifying therapeutic targets has long been a critical challenge in preventing and controlling PED through nutritional interventions. In the present study, 100 seven-day-old crossbred (Duroc \u00d7 Landrace \u00d7 Large White) healthy piglets from seven independent trials were selected for the experiment. The transcriptomics, proteomics, and metabolomics analyses were conducted on the small intestine and blood of piglets infected with PEDV, and the combined multiple batches of data were subsequently subjected to integrated analysis. Our findings revealed that PEDV infection significantly affected intestinal cell metabolism, especially lipid metabolism. Among those, sphingolipid and lysophospholipid metabolism could be potential pathways for preventive and therapeutic interventions. Additionally, retinol metabolism, mineral absorption, amino acid metabolism, and pyrimidine metabolism were remarkably altered following PEDV infection. Subsequently, candidate hub genes involved in the core pathways, such as apolipoprotein C3 (APOC3), cytochrome P450 family 3 subfamily A member 22 (CYP3A22), and intestinal alkaline sphingomyelinase (ENPP7), were identified and validated. In conclusion, the present study suggests that PEDV infection leads to the reprogramming of enterocyte lipid metabolism. Furthermore, manipulating lipid metabolism may influence the outcome of viral infection, highlighting potential targets for preventive and therapeutic interventions in managing viral infections.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Porcine epidemic diarrhea (PED) is a severe viral disease caused by the porcine epidemic diarrhea virus (PEDV), leading to huge economic losses in the swine industry. Identifying therapeutic targets has long been a critical challenge in preventing and controlling PED through nutritional interventions. The present study suggests that PEDV infection leads to the reprogramming of enterocyte lipid metabolism. Furthermore, manipulating lipid metabolism may influence the outcome of viral infection. The study also highlights potential targets for preventive and therapeutic interventions in managing viral infections.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01625-25","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T11:18:31Z","timestamp":1777547911000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Metabolic reprogramming in the enterocytes of neonatal piglets infected with porcine epidemic diarrhea virus: integrated omics and multi-batch analysis highlight alterations in lipid metabolism and potential therapeutic targets"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4032-167X","authenticated-orcid":false,"given":"Mengjun","family":"Wu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05w0e5j23","id-type":"ROR","asserted-by":"publisher"}],"name":"Hubei Key Laboratory of Animal 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