PURPOSE: Major cardiovascular surgery imposes high physiologic stress, often causing severe organ dysfunction and poor outcomes. The underlying mechanisms remain unclear. This study investigated metabolic changes induced by major cardiovascular surgery and the potential role of identified metabolic signatures in postoperative acute kidney injury (AKI). METHODS: A prospective observational study included 53 patients undergoing major cardiovascular surgery in 3 groups: cardiac surgery with cardiopulmonary bypass (CPB n = 33), without CPB (n = 10), and major vascular surgery (n = 10). For each patient, peripheral blood samples were collected pre-surgery, and at 6 h and 24 h post-surgery. Untargeted metabolomics using mass spectrometry quantified 8668 metabolic features in serum samples. Linear mixed-effect models (adjusted for age, sex, and body mass index) and pathway analyses were performed. RESULTS: In the cardiac surgery with CPB group, 772 features were significantly altered (P <
2.8E - 05) across the 3 time points. These features were enriched in five classes, all related to protein metabolism, with glycine and serine metabolism being the most represented. Cardiac surgery with CPB showed a distinct metabolic signature compared to other groups. Patients who developed postoperative AKI exhibited increased protein catabolism (including valine, leucine, and isoleucine degradation), disruptions in the citric acid cycle, and plasmatic accumulation of acylcarnitines. CONCLUSION: Major cardiovascular surgery, particularly with CPB, induces significant changes in protein metabolism. Patients developing postoperative AKI exhibited specific metabolic signatures. These findings may be critical for designing interventions to minimize organ dysfunction, including AKI, and improve outcomes in major cardiovascular surgery.