Background <p>Gastric cancer (GC) remains a common malignant tumor of the digestive system, with persistently high incidence and mortality rates. Therefore, new and effective therapeutic strategies are urgently needed to improve its treatment.</p> Methods <p>We investigated the anti-GC effect and underlying mechanism of the small molecule compound ETP-46321. In vitro functional assays were performed to evaluate the effects of ETP-46321 on GC cell proliferation, migration, and apoptosis. RNA sequencing was employed to elucidate the potential molecular mechanism of ETP-46321 treatment. SAT1 knockdown was used to investigate its impact on the effect of ETP-46321 in GC cells, and overexpression of SAT1 was also utilized. Bioinformatics analysis was used to explore the related signaling pathways. IGF-1 intervention was used as a rescue experiment to explore the role of the PI3K/AKT signaling pathway in the anti-tumor effect of ETP-46321. Finally, organoid and nude mouse xenograft models were used to verify the anti-GC activity of ETP-46321.</p> Results <p>ETP-46321 significantly inhibited the proliferation and migration of GC cells and induced cell apoptosis. Mechanistically, ETP-46321 could induce ferroptosis by upregulating SAT1. Knockdown of SAT1 reversed ETP-46321-mediated ferroptosis and restored cell proliferation and migration. Furthermore, ETP-46321 effectively inhibited the activity of the PI3K/AKT/mTOR signaling pathway, and this anti-cancer effect could be partially reversed by IGF-1, an activator of the PI3K/AKT/mTOR pathway. Both organoid and nude mouse xenograft models revealed the significant anti-GC activity of ETP-46321.</p> Conclusions <p>This study reveals a dual mechanism by which ETP-46321 exerts anti-GC effects by promoting SAT1-mediated ferroptosis and inhibiting the PI3K/AKT/mTOR signaling pathway. These findings provide important experimental evidence and theoretical support for the development of targeted GC therapies based on the mechanism of action of ETP-46321.</p>