Plasma acylcarnitine dysregulation associated with CPT1-mediated metabolism contributes to oral carcinogenesis

Growing evidence suggests that lipid metabolic reprogramming occurs in oral cancer (OC). We characterized circulating metabolic alterations associated with lipid metabolic reprogramming in OC. Semi-targeted and targeted plasma metabolomic profiling was performed in a discovery cohort (182 OC, 364 healthy controls [HC]) followed by independent external validation (52 OC, 52 HC). Machine learning approaches were used to identify plasma metabolites with strong discriminatory performance between patients with OC and healthy controls. Targeted validation confirmed consistent metabolic changes. Namely, three medium-chain acylcarnitines-decanoyl-, octanoyl-, and hexanoylcarnitine-were markedly downregulated in OC plasma, demonstrating consistent and reproducible discrimination during external validation (AUC = 0.941, 95% CI: 0.877-0.988). Pathway enrichment analysis further suggested altered β-oxidation and glycerophospholipid metabolism in OC. We also observed elevated carnitine palmitoyltransferase 1 (CPT1) expression in OC tissues and cells. Moreover, pharmacological inhibition of CPT1 suppressed OC cell growth and altered acylcarnitine profiles. These findings support an association between circulating acylcarnitine alterations and CPT1-related lipid metabolic reprogramming in OC. Furthermore, they provide biological context supporting the association between circulating metabolic alterations and CPT1-related lipid metabolic reprogramming in OC.