Background <p>Gastric cancer (GC) remains one of the most lethal malignancies worldwide, characterized by high morbidity and mortality rates due to its aggressive progression and limited therapeutic options. Understanding the molecular mechanisms underlying GC pathogenesis is crucial for identifying therapeutic targets. This study aimed to uncover key genes involved in GC progression and explore their functional roles and the underlying mechanism.</p> Methods <p>Differentially expressed genes (DEGs) between GC and normal gastric tissues were identified using the GSE66229 dataset. Functional enrichment analysis was performed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Weighted gene co-expression network analysis (WGCNA) and machine learning algorithms (LASSO and Random Forest) were applied to screen hub genes. The CIBERSORT algorithm was used to evaluate immune cell infiltration. mRNA and protein expression was validated using quantitative real-time polymerase chain reaction and Western blotting, respectively. Functional assays, including colony formation (proliferation), transwell (migration/invasion), sphere formation (stemness), and detection of ferroptosis markers (Fe²⁺, GSH, and ROS), were conducted to assess the malignant phenotypes of GC cells. The m6A modification mechanism was explored through RNA immunoprecipitation, m6A RNA immunoprecipitation-qPCR, and mRNA stability assays. In vivo experiments were performed using a xenograft mouse model to determine STIL’s role in tumor formation.</p> Results <p>A total of 385 DEGs (122 upregulated, 263 downregulated) were identified, with enrichment in extracellular matrix organization, cell cycle, and immune-related pathways. WGCNA and machine learning highlighted STIL centriolar assembly protein (STIL) as a key oncogene, which was significantly upregulated in GC tissues and cells. STIL knockdown suppressed proliferation, migration, invasion, and stem-like properties while promoting ferroptosis. In vivo, STIL silencing reduced tumor growth, accompanied by decreased STIL and GPX4 mRNA expression in tumor tissues. Mechanistically, RNA binding motif protein 15 (RBM15)-mediated m6A modification stabilized STIL mRNA. RBM15 knockdown inhibited the malignant phenotypes of GC cells by downregulating STIL. Immune analysis revealed correlations between STIL expression and infiltrating immune cells.</p> Conclusion <p>This study identifies STIL as a critical oncogene in GC, driven by RBM15-dependent m6A methylation. Targeting the RBM15-STIL axis may offer a novel therapeutic strategy for GC.</p>