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Introduction: Metabolic reprogramming is a hallmark of cancer. Plasma metabolomics offers a minimally invasive approach for identifying metabolic alterations that may provide insights into tumor progression.

Objectives: We aimed to characterize plasma metabolomic profiles in patients with oral squamous cell carcinoma (OSCC) and evaluate their clinical relevance.

Methods: Plasma samples from 43 OSCC patients and 129 cancer-free controls, matched at a 1:3 ratio based on age, sex, and body mass index, were analyzed using gas chromatography-mass spectrometry (GC-MS). A random forest algorithm was applied to identify key metabolic features distinguishing OSCC from controls. The clinical significance of the top metabolites was assessed and validated in another OSCC cohort (n = 27).

Results: A total of 113 compounds were putatively annotated and analyzed based on relative abundances. A ten-feature panel demonstrated good classification performance (area under the curve = 0.87; Matthews correlation coefficient = 0.703). The ten features are maltose, glucose, xylulose, δ-gluconolactone, fructose, indoleacetic acid, α-hydroxybutyric acid, glutamic acid, cysteine, and the monoacylglyceride MG(18:1(9Z)/0:0/0:0), suggesting dysregulated carbohydrate metabolism and oxidative stress as the major plasma metabolomic alterations in OSCC. Notably, α-hydroxybutyric acid levels were elevated in patients with regional lymph node metastasis compared with those without.

Conclusion: Our findings underscore the intricate interplay between altered glucose metabolism, redox imbalance, and OSCC. α-hydroxybutyric acid, a marker of oxidative stress and an indicator of insulin resistance, may be associated with metastatic progression.