Dysregulation of glucose-6-phosphate dehydrogenase in head and neck squamous cell carcinoma: Pathways, mutations, and therapeutic opportunities

Glucose-6-phosphate dehydrogenase ( G6PD) deficiency, the most common human enzyme defect, confers malaria resistance and is linked to reduced cancer risk. Its upregulation in malignancies suggests a critical role in tumour progression. This study examines G6PD in head and neck squamous cell carcinoma (HNSCC), focusing on its expression, genetic alterations, interactions, and therapeutic potential. Bioinformatics tools, including UALCAN, Human Protein Atlas, GEPIA2, cBioPortal, muTarget, GeneMANIA, Cancer Hallmarks, and GSCA, were used to analyse expression, survival, genomic alterations, protein interactions, pathway enrichment, and drug sensitivity. G6PD is significantly upregulated in HNSCC, correlating with poor overall and disease-free survival. Genomic alterations predominantly involve amplification, while regulatory mutations in NFE2L2 and KEAP1 increase expression, and mutations in HRAS and TACC2 reduce it. Protein interaction analysis links G6PD to oxidative stress, tumour metabolism, and cell migration, with key interactions involving NFE2L2 and HRAS. Enrichment analysis associates G6PD with metastasis, immune evasion, and metabolic reprogramming. Drug sensitivity analysis reveals a complex relationship between G6PD expression and therapeutic response. G6PD is critical in HNSCC progression and may serve as a prognostic biomarker and therapeutic target. Further experimental validation is required to explore G6PD inhibition as a treatment strategy, highlighting the importance of metabolic reprogramming in cancer therapy. • G6PD expression is upregulated in HNSCC, supporting tumour survival and growth. • High G6PD levels correlate with poor prognosis and reduced patient survival. • Genetic mutations regulate G6PD, influencing redox balance and tumour progression. • Protein interaction networks link G6PD to key cancer hallmarks and metabolic reprogramming. • G6PD inhibition shows promise for reducing cancer cell survival and metastasis.