β-Ionone promotes ferroptosis of human gastric cancer cells by inhibiting the Wnt/β-catenin pathway in vitro and in vivo.

β-Ionone (BI) has shown the potent inhibitory malignant progression of multiple tumors including gastric cancer in vitro and in vivo. However, the mechanism by which BI inhibits gastric cancer remains to be clarified, especially in ferroptosis, which is a new form of programmed cell death. The aim of this study was to investigate whether BI could induce ferroptosis in gastric cancer and the underlying mechanisms. The results manifested that BI obviously inhibited cell viability and increased the Fe2 + level, total reactive oxygen species (ROS) and lipid ROS levels and the malondialdehyde (MDA) concentrations, but reduced the mitochondrial membrane potential (MMP) and the expression of SLC7A11 and GPX4 in MKN45 cells and AGS cells (P < 0.05 or P < 0.01). Besides, BI also arrested cell cycle and decreased the expression of Cyclin D1 and CDK4 (P < 0.05 or P < 0.01). Mechanistically, BI reduced the levels of β-catenin and pGSK-3β/GSK-3β in MKN45 cells and AGS cells (P < 0.05 or P < 0.01). Nevertheless, pretreatment with lithium chloride (LiCl), an inhibitor of GSK-3β, reversed BI-induced ferroptosis and cell cycle arrested in MKN45 cells (P < 0.05). In addition, BI effectively inhibited the growth of gastric cancer xenografts and downregulated the levels of GPX4, SLC7A11, PCNA, β-catenin and pGSK-3β/GSK-3β (P < 0.05 or P < 0.01). Collectively, our study reveals that BI inhibits proliferation of gastric cancer cells by induction ferroptosis via the Wnt/β-catenin signaling pathway and provides a novel therapy for gastric cancer.