RBM8A confers oxaliplatin resistance in gastric cancer by maintaining EGFR mRNA stability.

RNA-binding proteins (RBPs) critically regulate post-transcriptional gene expression, yet their roles in chemotherapy resistance remain underexplored. Here, through a targeted siRNA screen of 40 RBM family members, we identified RNA-binding motif protein 8 A (RBM8A) as central orchestrator of oxaliplatin-induced DNA damage in gastric cancer (GC). Functional studies demonstrated that RBM8A promotes tumor proliferation and chemoresistance by recruiting the RNA helicase eIF4A3 to stabilize epidermal growth factor receptor (EGFR) mRNA, shielding it from exonucleolytic degradation. This stabilization sustains EGFR protein levels, enabling nuclear EGFR-DNA-PKcs complex formation to drive non-homologous end joining (NHEJ)-mediated DNA repair and suppress oxaliplatin-induced apoptosis. Therapeutic targeting of this axis with the EGFR inhibitor gefitinib restored oxaliplatin sensitivity in vitro and synergistically suppressed RBM8A-driven xenograft growth in vivo. Additionally, single-cell RNA-seq revealed RBM8A enrichment in malignant gastric epithelial cells, while tissue microarrays confirmed that dual RBM8A/EGFR overexpression predicts the poorest survival outcomes. Collectively, our findings define the RBM8A-eIF4A3-EGFR axis as a druggable determinant of chemoresistance and establish RBM8A as both a prognostic biomarker and therapeutic target in GC.