Background <p>Gastric cancer (GC) is a highly heterogeneous malignancy with poor prognosis, and reliable biomarkers for prognostic stratification and therapeutic guidance remain limited. Although ZNF469 has been implicated in fibrotic processes, its expression pattern, clinical significance, and biological role in GC remain unclear.</p> Methods <p>Public GC transcriptomic datasets were analyzed to identify differentially expressed genes and prognostic candidates. Functional enrichment, Gene alteration, immune infiltration, single-cell RNA sequencing, spatial transcriptomic, and drug sensitivity analyses were subsequently performed to characterize the biological significance of ZNF469. In addition, qPCR was used to validate ZNF469 expression in normal and tumor tissues, and siRNA-mediated knockdown assays were conducted to evaluate its effect on HGC-27 cell proliferation.</p> Results <p>ZNF469 was identified as an upregulated gene in GC and was associated with unfavorable prognosis. qPCR validation confirmed its elevated expression in tumor tissues, and silencing of ZNF469 inhibited HGC-27 cell proliferation. Functional enrichment analyses indicated that ZNF469 was associated with multiple malignant pathways. Moreover, ZNF469 expression correlated with stromal and immune features of the tumor microenvironment. Single-cell and spatial transcriptomic analyses further showed that ZNF469 was predominantly enriched in fibroblast populations, suggesting a potential role in cancer-associated fibroblast-related microenvironmental remodeling. In addition, ZNF469 expression was associated with drug sensitivity, indicating its potential relevance for therapeutic stratification.</p> Conclusions <p>ZNF469 is a potential prognostic biomarker associated with poor outcome and microenvironmental remodeling in GC. Our findings suggest that ZNF469 may contribute to GC progression through both tumor-intrinsic and fibroblast-associated mechanisms.</p>