Metabolic Reprogramming Across Molecular Subtypes of Gastric Cancer

Abstract Purpose Gastric cancer molecular subtypes defined by The Cancer Genome Atlas — chromosomal instability (CIN), microsatellite instability (MSI), genomically stable (GS), and Epstein-Barr virus-positive (EBV) — carry distinct biological features, yet their metabolic programmes and clinical significance remain uncharacterised across all four subtypes simultaneously. Methods Gene Set Variation Analysis (GSVA) was applied to RNA-sequencing data from 383 TCGA gastric adenocarcinomas to quantify activity of six core metabolic pathways: glycolysis, oxidative phosphorylation, fatty acid oxidation (FAO), the pentose phosphate pathway (PPP), glutamine metabolism, and lactate metabolism. Subtype-specific survival associations were assessed by continuous Cox proportional hazards regression with multivariable adjustment. Transcriptional regulatory mechanisms were investigated through expression analysis of 20 metabolic transcription factors. External validation was performed in the independent ACRG cohort (GSE62254; n=300). Results All six pathways showed significant subtype stratification (Kruskal-Wallis, all FDR<0.001). Within GS tumours, elevated FAO activity was independently associated with worse overall survival after multivariable adjustment (HR=7.261, 95% CI: 1.604–32.865, P=0.010). Within MSI tumours, elevated PPP (HR=0.211, P=0.014) and glutamine pathway activity (HR=0.169, P=0.019) were associated with improved survival, potentially reflecting antioxidant support of anti-tumour immunity. PRKAA2, SREBF1, and MYC were identified as key subtype-specific transcriptional regulators. Cross-platform validation confirmed direction preservation of metabolic pathway coordination in 13 of 15 pathway pairs in the ACRG cohort. Conclusions Gastric cancer molecular subtypes exhibit distinct metabolic vulnerabilities with independent prognostic significance. The GS-FAO association identifies a high-risk metabolic phenotype amenable to CPT1 inhibitor evaluation, while MSI biosynthetic pathway elevation may underpin immune checkpoint sensitivity.