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To better understand its onset, untargeted serum metabolomics and lipidomics are analyzed from 152 presymptomatic patients undergoing major elective surgery, and identified key metabolites, including serine and aminoadipic acid, that differentiate postoperative uncomplicated infection from sepsis. Using single\u2010nucleus RNA sequencing data from an in vivo mouse model of sepsis, tissue\u2010independent down\u2010regulation and tissue\u2010specific differences of serine and energy\u2010related genes including key module roles for the mitochondria\u2010linked genes,\n                    <jats:italic>Cox4i1<\/jats:italic>\n                    ,\n                    <jats:italic>Cox8a<\/jats:italic>\n                    , and\n                    <jats:italic>Ndufa4<\/jats:italic>\n                    are identified. Finally, serine\u2010dependent metabolic shifts, especially in the liver, are revealed by using\n                    <jats:sup>12<\/jats:sup>\n                    C\/\n                    <jats:sup>13<\/jats:sup>\n                    C murine data with labeled serine, and link altered activity of the serine hydroxymethyltransferase (SHMT) cycle with perturbed purine metabolism during sepsis. This study demonstrates the close interrelationship between early metabolite changes and mitochondrial dysfunction in sepsis, improves the understanding of the underlying pathophysiology, and highlights metabolic targets to prospectively treat presymptomatic, but at\u2010risk, patients.\n                  <\/jats:p>","DOI":"10.1002\/advs.202504418","type":"journal-article","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T07:04:33Z","timestamp":1748070273000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Multi\u2010Omics and \u2010Organ Insights into Energy Metabolic Adaptations in Early Sepsis Onset"],"prefix":"10.1002","volume":"12","author":[{"given":"Lin\u2010Lin","family":"Xu","sequence":"first","affiliation":[{"name":"Microbiome Dynamics Leibniz Institute for Natural Product Research and Infection Biology\u2013 Hans Kn\u00f6ll Institute  07745 Jena 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