Unveiling the oncogenic role of PDK3 in head and neck squamous cell carcinoma, an integrative in silico and an in vitro approach.

Head and neck squamous cell carcinoma (HNSCC) is a clinically aggressive malignancy with a poor prognosis. Emerging evidence highlights the importance of metabolic reprogramming in tumor progression and therapy resistance. However, the mechanisms driving metabolic adaptation in HNSCC remain incompletely understood. Here, we investigate pyruvate dehydrogenase kinase 3 (PDK3), a regulatory enzyme critical for aerobic glycolysis (the Warburg effect) in cancer cells. Using computational analysis and experimental validation, we explored PDK3's role as an oncogene in HNSCC. Our gene expression analysis revealed that PDK3 is significantly upregulated in tumors compared to normal tissues. Pathway enrichment analysis linked PDK3 to key metabolic pathways essential for cellular energy production and biosynthesis, including the TCA cycle, pyruvate metabolism, and glycolysis/gluconeogenesis. Additionally, PDK3 upregulation influenced immune cell distribution and drug response. Clinically, elevated PDK3 expression correlated with reduced overall survival in patients. Functional validation in an HNSCC cell line (HSC3) demonstrated that PDK3 knockdown suppressed growth, proliferation, and migration, suggesting PDK3's role as a potential tumor promoter in HNSCC. These findings indicate that targeting PDK3 could be a promising therapeutic strategy for HNSCC management.