Sanguinarine Inhibits Gastric Cancer Progression by Targeting the NOS2/SOD1 Axis to Promote Ferroptosis

Ferroptosis, an iron-dependent form of non-apoptotic cell death, has emerged as a critical process in cancer therapy. Sanguinarine chloride (S.C), an alkaloid that stimulates apoptosis by activating reactive oxygen species (ROS), has demonstrated significant anticancer potential, but its role in modulating ferroptosis remains unclear. The aim of the present study was to elucidate the effects of S.C on ferroptosis in gastric cancer (GC) progression and its mechanism. Here, we determined cell viability by CCK-8 and revealed that the most potent drug, S.C, which is a small molecule compound in the ferroptosis library, had the strongest killing effect on GC cells. S.C could trigger ferroptosis in GC cells by inhibiting glutathione levels through promoting malondialdehyde production and ROS accumulation. Interestingly, S.C was found to function as a pro-ferroptotic death by interacting with NOS2 through network pharmacological docking. Mechanistically, we observed the deacetylase SIRT1 to regulate the acetylation level of NOS2 and thus affect the expression of NOS2. In addition, S.C regulates the downregulation of SLC7A11 and GPX4 through the SIRT1/NOS2/SOD1 pathway, and thereby induces ferroptosis. <i>In vivo</i> experiments showed that S.C treatment significantly inhibited subcutaneous tumor growth in BALB/c nude mice. This was significantly rescued by injection of a ferroptosis rescue agent (AA9). Taken together, these findings demonstrate that S.C works through the SIRT1/NOS2/SOD1 pathway and suggest that targeting SLC7A11/GPX4 to cause ferroptosis in cancer cells has potential as an anticancer therapy.