BackgroundFusobacterium nucleatum(F. nucleatum) is a vital pro-oncogenic bacterium. Our previous study revealed that a high abundance ofF. nucleatumin head and neck squamous cell carcinoma (HNSCC) is correlated with poor patient prognosis. However, the impact ofF. nucleatumon metabolic reprogramming and tumor progression in HNSCC awaits more exploration.MethodsLiquid chromatography‒mass spectrometry (LC‒MS) was applied to analyze the altered metabolites in a head and neck carcinoma cell line (AMC-HN-8) after coculture withF. nucleatumfor 24 hrs and 48 hrs. Both univariate and multivariate analyses were used to screen for differential metabolites. Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway enrichment analysis was further used to explore the metabolic changes.ResultsWe observed a significantly altered metabolic profile in AMC-HN-8 cells over time after coculture withF. nucleatum. Among the several enriched pathways, the purine metabolic pathway was the most significantly enriched (P= 0.0005), with downregulation of purine degradation. Furthermore, uric acid, the end product of purine metabolism, significantly reversedF. nucleatum-triggered tumor progression and altered the intracellular reactive oxygen species (ROS) level. Moreover, the negative correlation between the serum uric acid level and the abundance ofF. nucleatumwas verified in 113 HNSCC patients (P= 0.0412, R = − 0.1924).ConclusionsOur study revealed obviously aberrant purine metabolism driven byF. nucleatumin HNSCC, which was closely related to tumor progression and patient prognosis. These findings indicate the possibility of targetingF. nucleatum-induced purine metabolism reprogramming in the future treatment of HNSCC.