Integrative analysis identifies ALDOA and PGK1 as prognostic biomarkers and therapeutic targets in oral squamous cell carcinoma

BACKGROUND: Oral squamous cell carcinoma (OSCC) is associated with high mortality and limited effective targeted therapies. Although metabolic reprogramming is closely linked to malignancy, the key metabolic regulators that functionally drive OSCC progression and may serve as therapeutic targets remain incompletely defined. METHODS: We combined clinical transcriptomic analysis with functional genomic screening to identify metabolic vulnerabilities in OSCC. A Least Absolute Shrinkage and Selection Operator (LASSO)-derived prognostic gene signature was constructed using transcriptomic data from The Cancer Genome Atlas (TCGA)-OSCC cohort. To prioritize functionally critical targets, gene essentiality and tumor selectivity were evaluated using large-scale CRISPR-Cas9 dependency data from the Cancer Dependency Map (DepMap) project. RESULTS: This analysis identified Aldolase A (ALDOA) and Phosphoglycerate Kinase 1 (PGK1) as candidate targets with prognostic relevance and strong dependency across OSCC cell lines. Elevated expression of ALDOA and PGK1 was significantly associated with poor patient survival. Mechanistically, genetic silencing of ALDOA or PGK1 impaired glycolytic activity, as evidenced by reduced extracellular acidification rates (ECAR), and suppressed tumor cell proliferation in vitro and in vivo. Furthermore, combined targeting of these two glycolytic enzymes produced synergistic anti-tumor effects. Bliss independence analysis showed synergy between the ALDOA inhibitor Aldometanib and the PGK1 inhibitor CBR-470-1, and the combination produced greater tumor suppression than either monotherapy in xenograft models. CONCLUSION: Our findings indicate that ALDOA and PGK1 contribute to metabolic reprogramming and poor prognosis in OSCC. These findings support further evaluation of dual ALDOA and PGK1 inhibition as a potential therapeutic strategy for OSCC.