GNAS drives gastric cancer progression via pyrimidine metabolic reprogramming and immune-microenvironment remodeling

Metabolic reprogramming, particularly the altered nucleotide metabolism, is a critical driver of tumor heterogeneity and malignant progression in gastric cancer (GC). However, the core molecular determinants orchestrating this metabolic shift and its subsequent impact on the tumor microenvironment (TME) remain elusive. We integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA-seq data to delineate the metabolic landscape of GC. The metabolic vulnerabilities and functional roles of the identified hub gene were systematically validated using in vitro assays, in vivo xenograft models, and pharmacological metabolic interventions. Pathway-level metabolic flux inference via scRNA-seq revealed a pronounced shift toward nucleotide interconversion and pyrimidine synthesis in malignant epithelial cells. We identified GNAS as a key metabolic hub gene, which is consistently upregulated in highly malignant subsets and strongly predictive of poor patient survival. Pseudotime and spatial transcriptomic analyses demonstrated that GNAS⁺ epithelial cells occupy terminally differentiated malignant states and specifically localize within spatial niches characterized by hyperactive nucleic acid metabolism and an immunosuppressive TME driven by cancer-associated fibroblasts (CAFs). Mechanistically, GNAS depletion profoundly impaired pyrimidine nucleotide (UMP/UDP) biosynthesis, which sequentially attenuated the activity of the ATF3-JUN-ETS1 transcriptional network, leading to suppressed GC cell proliferation, migration, and invasion, alongside induced apoptosis. Notably, exogenous uridine supplementation successfully rescued these malignant phenotypes, whereas pharmacological inhibition of pyrimidine synthesis (DHODH inhibitor) abolished the oncogenic advantage conferred by GNAS overexpression. GNAS is associated with the malignant evolution of GC by driving pyrimidine metabolic reprogramming and spatially coordinating TME remodeling. Targeting the GNAS-mediated metabolic-transcriptional axis exposes a novel therapeutic vulnerability, offering a promising translational strategy for precision oncology in GC.