PDK4 as a tumor suppressor in gastric cancer: implications for metabolic regulation, immune modulation, and...

Gastric cancer (GC) remains a leading cause of cancer-related mortality, with growing evidence implicating metabolic regulators in its progression. This study investigates the expression pattern, prognostic significance, molecular interactions, and immunomodulatory role of pyruvate dehydrogenase kinase 4 (PDK4) in GC.

Integrated bioinformatics analyses were conducted using RNA sequencing and clinical data from the TCGA-STAD and GSE54129 datasets. Differential gene expression analysis identified co-differentially expressed genes (co-DEGs). Functional enrichment analysis, protein-protein interaction (PPI) network construction, competing endogenous RNA (ceRNA) network prediction, and immune infiltration analysis were performed. The clinical relevance of PDK4 was evaluated through survival analysis, Cox regression modeling, and receiver operating characteristic (ROC) curve analysis.

PDK4 expression was significantly downregulated in GC tissues compared to normal controls (P < 0.001), while its high expression was associated with advanced tumor stage (P = 0.0322) and favorable prognosis (P = 0.0013). A total of 77 co-DEGs and PDK4-centered PPI networks highlighted its involvement in key metabolic pathways, including the tricarboxylic acid (TCA) cycle, AMPK signaling, and HIF-1 signaling. The ceRNA network analysis identified 135 miRNAs and 225 lncRNAs associated with PDK4, including KCNQ1OT1. Immune infiltration analysis revealed a positive correlation between PDK4 expression and B cell (r = 0.249) and CD4⁺T cell (r = 0.419) abundance, suggesting an immunoregulatory role. PDK4 exhibited high diagnostic accuracy (AUC = 0.775 in TCGA) and emerged as an independent prognostic factor (P = 0.004, HR = 1.159).

PDK4 functions as a tumor suppressor in GC, bridging metabolic reprogramming, epigenetic regulation, and immune microenvironment remodeling. Its downregulation contributes to disease progression and immune evasion, underscoring its potential as a prognostic biomarker and therapeutic target. Restoring PDK4 activity may serve as a promising strategy to mitigate GC aggressiveness and therapeutic resistance.