Single-Cell Transcriptomic Analysis Identifies an OLFM4-Associated Gastric Cancer Cell State with...

Gastric adenocarcinoma (STAD) exhibits extensive intratumoral heterogeneity that contributes to tumor progression and therapeutic resistance. In this study, we integrated single-cell RNA sequencing and bulk transcriptomic analyses to characterize malignant epithelial subtypes in STAD. Among seven identified tumor subtypes, the OLFM4-associated C3 subtype exhibited enriched palmitoylation-related signatures and altered metabolic activities, particularly glycolysis-related pathways. Functional enrichment analyses further supported the enrichment of multiple energy metabolism pathways. To evaluate the association between OLFM4 and metabolic regulation, recombinant OLFM4 treatment and siRNA-mediated OLFM4 knockdown were performed in gastric cancer cell lines. OLFM4 upregulation increased the expression of ZDHHC2 and GLUT1, accompanied by enhanced glucose uptake and elevated ATP production, whereas OLFM4 silencing reduced ZDHHC2 and GLUT1 expression. In addition, a prognostic risk model derived from C3 subtype-associated genes (MUC16, RALA, and PCBD1) effectively stratified STAD patients and was associated with immune checkpoint expression and immune infiltration. Collectively, our findings identify an OLFM4-associated gastric cancer cell state with palmitoylation-related signatures and altered metabolic activities, highlighting its potential relevance to metabolic heterogeneity in gastric adenocarcinoma.