‌PPIA regulates fatty acid and glutamine metabolism in lung adenocarcinoma based on multiomics prognostic model and...

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer worldwide, in which fatty acid metabolism plays a key role in tumor growth, metastasis, and immune evasion. PPIA has been confirmed to be closely related to tumor metabolism and immune regulation, but its specific mechanism of action is still unclear. Multi-omics data from TCGA and GEO, combined with single-cell RNA sequencing (scRNA-seq), were used to characterize metabolic heterogeneity and the immune microenvironment in lung adenocarcinoma (LUAD). Fatty acid metabolism–related genes were identified via WGCNA and univariate Cox regression, and a prognostic risk model was constructed. Virtual knockout, cell function assays, and metabolic profiling were performed to investigate the role of PPIA in metabolic reprogramming and tumor progression. In vitro, PPIA was silenced using siRNA or co-overexpressed with pCMV-C-Myc in A549 and H1975 cells. Functional validation included qRT-PCR and Western blotting, as well as CCK-8, colony formation, wound healing, and Transwell assays to assess proliferation, migration, and invasion. Metabolic assays measured glutamine uptake, α-ketoglutarate production, free fatty acid levels, and the GSH/GSSG ratio, elucidating PPIA’s regulatory effects on metabolism and LUAD progression. Integrative multi-omics analysis identified a fatty acid metabolism–related gene module associated with poor prognosis in LUAD. A four-gene risk model (ERCC1, KYNU, AKR1A1, and PPIA) demonstrated strong predictive power for overall survival across multiple datasets. Single-cell analysis revealed that PPIA was highly expressed in malignant, metabolically active cell populations and strongly correlated with fatty acid and glutamine metabolism. Functional assays confirmed that PPIA silencing inhibited LUAD cell proliferation, migration, and EMT, while reducing key metabolites including glutamine uptake, α-ketoglutarate, free fatty acids, and the GSH/GSSG ratio. Mechanistically, PPIA depletion downregulated c-Myc expression, whereas c-Myc overexpression partially reversed these effects, suggesting that PPIA drives LUAD progression through the c-Myc–mediated fatty acid–glutamine metabolic axis. This study reveals that PPIA promotes the malignant progression of LUAD and affects the immune microenvironment by regulating the c-Myc-mediated fatty acid-glutamine metabolism network remodeling. A prognosis model based on fatty acid metabolism can serve as an effective tool for assessing the prognosis of LUAD patients. Due to incomplete clinical information in some datasets, comprehensive subgroup analyses could not be performed.