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Using comprehensive metabolomic profiling via ultra-performance liquid chromatographymass spectrometry in well-established HPV-positive (SCC47, SCC104) and HPV-negative (Detroit562, SCC9) HNSCC cell lines, we demonstrate for the first time through comprehensive metabolomic analysis that HPV-positive HNSCC uniquely enhances metabolic pathways advantageous for rapid cell proliferation, including glycolysis and nicotinamide metabolism