Association of pyruvate metabolism-related genes with immune infiltration and prognostic value in lung adenocarcinoma.

Abstract

Pyruvate metabolism-related genes (PMRGs) play important roles in tumorigenesis and the tumor microenvironment. However, their prognostic value and biological relevance in lung adenocarcinoma (LUAD) remain unclear. LUAD transcriptomic, mutation, and clinical data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus (GSE31210 and GSE72094), and PMRGs from Kyoto Encyclopedia of Genes and Genomes. Differentially expressed PMRGs were identified by intersecting LUAD-related differentially expressed genes with PMRGs. Prognostic modeling, external validation, functional enrichment, immune infiltration, tumor mutation burden, and drug sensitivity analyses were performed. Based on PMRG expression, we established a 12-gene prognostic signature that effectively stratified patients with LUAD into high- and low-risk groups in The Cancer Genome Atlas training cohort and GSE72094 validation cohort. The Risk Score was confirmed as an independent prognostic factor for LUAD. Quantitative real-time reverse transcription PCR of 3 paired LUAD and adjacent normal tissues showed expression trends broadly consistent with bioinformatics results, but the small sample size precluded clinical validation. The low-risk group exhibited higher immune cell infiltration and potentially better immunotherapy responsiveness, whereas the high-risk group showed greater predicted sensitivity to bleomycin and doxorubicin. In vitro experiments further demonstrated that aldehyde dehydrogenase 1 family member B1 (ALDH1B1), a key signature gene, promoted LUAD cell proliferation, colony formation, migration, and invasion. Functionally, ALDH1B1 may enhance malignant phenotypes at least partially by activating glycolytic metabolism. These experiments provide preliminary, gene-specific functional evidence for ALDH1B1 but cannot be regarded as biological validation of the full 12-gene prognostic signature. Overall, this PMRG-related signature may possess prognostic stratification value for LUAD; however, its complete biological basis and clinical application potential require further verification. SIGNIFICANCE STATEMENT: A 12-gene pyruvate metabolism-related signature showed prognostic stratification value in retrospective LUAD cohorts and was associated with differences in immune profiles and predicted drug sensitivity. Functional experiments further provided preliminary evidence linking ALDH1B1 to malignant cellular phenotypes and glycolytic activity. Further prospective and functional validation of the complete signature is required.