Abstract

Background 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. Methods 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. Results 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. Conclusions 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 supp