In the PDX model, terfenadine (10 mg/kg) significantly suppressed tumor growth, reducing final tumor weight by 41.2% (<i>p</i> < 0.001).<h4>Conclusion</h4>This study demonstrates that terfenadine exerts multifaceted antitumor effects in GC through modulation of the PI3K/AKT/mTOR pathway, exhibits synergistic activity with 5-Fu, and shows <i>in vivo</i> efficacy in a clinically relevant PDX model. Here, MTOR is linked to gastric cancer.