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We profiled longitudinal metabolic changes in adults without diabetes undergoing cardiac surgery to identify pathways associated with perioperative SH (defined as point-of-care glucose \u2265140 mg\/dL on \u22653 readings or \u2265180 mg\/dL once). Blood was collected at baseline before surgery (T0) and at 2 h (T1), 24\u201348 h (T2), and 72\u201396 h (T3) after surgical initiation. High-resolution metabolomics (LC\u2013MS) was integrated with continuous glucose monitoring and inflammatory\/cardiac biomarkers. At T0, several pathways were associated with subsequent SH, including bile acid metabolism, the carnitine shuttle, and fatty-acid oxidation, suggesting preoperative metabolic susceptibility. In longitudinal analyses, participants who developed SH showed coordinated postoperative changes with significant enrichment of pathways not evident at baseline, C21-steroid hormone biosynthesis, glycerophospholipid metabolism, and glycosphingolipid (ceramide) metabolism, consistent with lipid remodeling and inflammatory signaling during surgical stress. Individuals with SH also exhibited higher inflammatory biomarker levels (high-sensitivity C-reactive protein and soluble urokinase plasminogen activator receptor). A machine-learning model using early metabolomic features predicted SH with an area under the receiver operating characteristic curve of 0.86. These findings highlight distinct preoperative and perioperative metabolic trajectories associated with SH and implicate established dysglycemia-related pathways, as well as stress-induced pathways in perioperative metabolic dysregulation. Pathway enrichment analyses were exploratory and hypothesis-generating; validation in larger cohorts and assessment of implications for clinical outcomes are warranted.<\/jats:p>","DOI":"10.1101\/2025.09.16.676529","type":"posted-content","created":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T16:15:13Z","timestamp":1758384913000},"source":"Crossref","is-referenced-by-count":3,"title":["Metabolic Trajectories During Surgical Stress in Patients Undergoing Cardiac Surgery"],"prefix":"10.64898","author":[{"given":"Dohyun","family":"Ku","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackson","family":"Bartelt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Feeley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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