The potential of PDHA1 as a cuproptosis-related prognostic and immune biomarker in lung squamous cell carcinoma

BACKGROUND: Lung cancer is a leading cause of cancer death, with non-small cell lung cancer (NSCLC) being the most common type. Cuproptosis is poorly characterized in lung squamous cell carcinoma (LUSC). This study evaluated cuproptosis-related genes and the prognostic and biological roles of Pyruvate dehydrogenase E1 subunit alpha 1(PDHA1). METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) transcriptomic/clinical data were analyzed. After PDHA1 overexpression in HCC95 lung adenocarcinoma cells, colony formation, wound healing, flow cytometry, and xenograft assays were performed, including anti-PD-L1-treated groups. RESULTS: PDHA1 was differentially expressed in NSCLC. Higher PDHA1 in LUSC correlated with poorer overall survival (HR = 1.40), supported by GEO trends. PDHA1 correlated with oncogenic/immune pathways, immune infiltration, immunotherapy response in public non-LUSC-specific cohorts, RNA methylation regulators, stemness, genomic alterations, and predicted drug sensitivity. In HCC95 cells, PDHA1 overexpression increased colony formation, wound closure, altered cell-cycle distribution, and xenograft burden. CONCLUSIONS: Higher PDHA1 is associated with adverse prognosis and tumor-related molecular/immune features in LUSC. Experiments support a preliminary tumor-promoting association in an HCC95 model, but immunocompetent models and prospective clinical validation are needed before PDHA1 can be considered a therapeutic or immunotherapy-response biomarker.