Abstract
Metabolic reprogramming, a well-established hallmark of gastric carcinogenesis, has been implicated in driving tumor progression. Nevertheless, the precise mechanisms through which these metabolic alterations orchestrate gastric cancer (GC) pathogenesis remain incompletely elucidated. We conducted metabolomic analyses of plasma samples obtained from 334 patients with GC and healthy individuals to identify differential metabolites and metabolic pathways. Transcriptome sequencing was conducted on six pairs of tissues, and a joint analysis of the transcriptome and metabolome was performed. Single-cell sequencing data were acquired and co-analyzed with metabolomics to investigate metabolic abnormalities at the single-cell level. Finally, four representative metabolites selected using Random Forest analysis were subjected to cellular experiments to elucidate the mechanisms through which these metabolites exert their effects. Metabolomic analyses revealed that serine and glycine metabolism, glycolysis, and glutamate metabolism were significantly altered in GC, suggesting that one-carbon metabolism (1CM)-related pathways are aberrantly activated. A combined analysis of the transcriptome, single-cell transcriptome, and metabolomics indicated that pathways related to oxidative phosphorylation, nucleotide metabolism, and amino acid metabolism in epithelial cells were altered in GC. Cellular experiments demonstrated that the one-carbon donor metabolite betaine could inhibit the activity, invasion, and migration of GC cells while activating the phosphorylation of AMPKα. In conclusion, the 1CM-related pathway and the metabolite betaine play significant roles in GC, and the mechanisms through which the one-carbon donor betaine influences GC warrant further investigation.