Abstract
Head and neck squamous cell carcinoma (HNSCC) is a complex multivariable disease posing a significant challenge in therapeutics. OXPHOS and PPP are centrally implicated in metabolic heterogeneity influencing tumor behavior, treatment response, and patient outcomes. This study aims to stratify HNSCC based on OXPHOS and PPP gene expression to construct a clinical outcome risk predictive model. HNSCC patients were stratified into four metabolic subtypes including mixed, OXPHOS-leaning, PPP-leaning, and quiescent. The quiescent metabolic subtype showed longest survival with lower proliferation scores, whereas mixed subtype showed the worst survival with higher proliferation scores. Metabolic proteins of the CPTAC and ICPC cohorts affirmed the existence of metabolic heterogeneity among tumor samples. A prognostic risk predictive model was developed based on thirteen genes, which performed better than the OXPHOS-PPP-glycolysis model and other predictive forty-seven metabolic gene’s model. Existence of metabolic heterogeneity was successfully determined in HNSCC. OXPHOS and PPP genes enriched in mixed metabolic subtype having the worst clinical outcome are suggestive of higher metastatic potential, which might offer advisement in personalized therapeutics.

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Data availability
The proteomics dataset generated in this study has been deposited at the ProteomeXchange Consortium via the PRIDE83 partner repository with the dataset identifier PXD073947. The data analysis workflow and code is available at https://github.com/AK2-lab/Metabolic-Heterogeneity-Code/tree/main.
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Acknowledgements
We thank TCGA project and PDC portal for the availability of the transcriptome and proteome data of HNSCC cohort. AG thanks CSIR India for fellowship. The authors are grateful to Prof. Saumitra Das (Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru) for connecting us with clinicians. This research work was supported by BRIC-National Institute of Biomedical Genomic intramural funding (NIBMG-60116).
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Writing—Original draft preparation, S. Sau, A.G., S. Sinha, A.M.K.; Writing–Review and Editing, S.M.A.M., A.M.K.; Software and Methodology, S. Sau, A.M.K.; Investigation and conceptualization, S. Sau, A.M.K.; Supervision, A.M.K. All authors read and approved the final manuscript.
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Sau, S., Gupta, A., Sinha, S. et al. Metabolic gene expression-based stratification and prognostic risk predictive model of head and neck squamous cell carcinoma. npj Syst Biol Appl (2026). https://doi.org/10.1038/s41540-026-00689-0
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DOI: https://doi.org/10.1038/s41540-026-00689-0


