<p>Identification of potential prognostic biomarkers and therapeutic targets for gastric cancer (GC) remains crucial. We conducted an integrative analysis, utilizing single-cell transcriptome datasets concerning early GC from GEO database, along with DNA methylation data from UCSC Data Center, to screen for dysregulated genes in early GC. Our findings revealed that IFITM2 expression was up-regulated in early GC epithelial cells and its promoter methylation was down-regulated. Elevated IFITM2 levels were further confirmed in GC cell lines and GC tissues from TCGA patients. According to the TCGA database, a high level of IFITM2 was correlated with a poor prognosis in GC patients. Both Depmap single-gene CRISPR knockout screens across 35 GC cell lines and in house siRNA-mediated IFITM2 knockdown experiments demonstrated that IFITM2 silencing inhibited cell proliferation. GSEA analysis indicated that high levels of IFITM2 was enriched in TNFα signaling via NF-κB. Furthermore, STRING protein-protein interaction analysis suggested a functional link between IFITM2 and NF-κB. Finally, IFITM2 silencing significantly suppressed NF-κB activity and the expression of NF-κB targeted genes, including the anti-apoptotic genes BCL-2, BCL-XL, the pro-proliferation genes TNFα, CCL2, CDK1, and the pro-metastasis gene COX-2. Therefore, our study suggests that IFITM2 may promote the initiation and proliferation of GC by activating NF-κB signaling pathway, positioning IFITM2 as a prognostic biomarker and therapeutic target for GC.</p>