Importance <p>Childhood hypertension is a growing health problem, yet its specific biomarkers are not yet fully elucidated.</p> Objective <p>The aim of this study was to investigate the functional metabolic alteration associated with hypertension in late adolescents.</p> Design <p>This study employed a cluster random sampling method based on the Health Promotion Program for Children and Adolescents. In the first stage in 2020-2021, three schools were selected for hypertension screening, followed by four schools in the second stage in 2022-2023. Hypertensive students in their late adolescent were matched 1:1 with normotensive controls for an untargeted metabolomics study to identify differential metabolites. In vitro cellular experiments were further performed to explore the functional roles of the interested metabolite.</p> Setting <p>Two separate case-control studies and cellular experiments.</p> Participants <p>In the first stage, a total of 51 late adolescents were identified with hypertension, and then were matched with 51 normotensive controls of similar sex and age from the same dormitory to collect their fasting urine samples. In the second stage, 91 hypertensive adolescents were identified and 91 matched normotensive adolescents were selected from the same dormitory to collect their fasting serum samples.</p> Main outcomes and measures <p>Hypertension was diagnosed by blood pressure measurements taken on three separate occasions.</p> Results <p>Detailed metabolomic evaluation revealed four distinct metabolites differentially expressed in hypertensive adolescents and control individuals in both urine and serum samples. As compared with the control group, higher levels of 2-hydroxycinnamic acid and xanthine, but lower levels of hypoxanthine and N-acetylornithine were observed in hypertensive adolescents. These metabolites also slightly enhance the discriminatory ability for hypertension based on body mass index Z score, as revealed by increased area under receiver operating characteristic curve. Notably, 2-hydroxycinnamic acid could inhibit cell proliferation, induce oxidative stress and inflammatory responses, and then disrupt the cellular function of human umbilical vein endothelial cells, inferring it as a potential detrimental metabolite for hypertension in adolescents.</p> Conclusions and relevance <p>Our result revealed distinct metabolic alterations in urine and serum samples of hypertensive adolescents. Combined with metabonomic and in vitro experiments, 2-hydroxycinnamic acid was identified as a potential detrimental metabolite for hypertension in adolescents.</p>