Metformin-induced RBMS3 expression enhances ferroptosis and suppresses ovarian cancer progression.

Metformin (Met), a widely used type II diabetes medication, has shown anti-cancer properties in various cancers. RBMS3 is a tumor suppressor implicated in several cancers, including ovarian cancer. Ferroptosis, a novel form of programmed cell death, is gaining attention in cancer research. This study explores whether metformin induces ferroptosis and inhibits ovarian cancer progression through the RBMS3 pathway. We used a CCK-8 assay to determine the optimal metformin concentration for ovarian cancer cells. Metformin's effects were further evaluated using EdU assay and flow cytometry. To clarify its mechanism, we employed programmed cell death inhibitors and measured levels of MDA (Malondialdehyde), GSH (Glutathione), and Fe²⁺. Ferroptosis-related proteins and RBMS3 expression in ovarian cancer tissues and cells were assessed via RT-qPCR and Western blotting. A xenograft mouse model was used to observe metformin's effects on tumor growth. Metformin inhibited the viability of ovarian cancer A2780 cells, promoted ferroptosis, increased MDA and Fe²⁺ levels, and reduced GSH. It upregulated ferroptosis-related genes while downregulating GPX4 and SLC7A11. Although RBMS3 was reduced in cancer cells, metformin increased its expression, and silencing RBMS3 reversed metformin's effects. In vivo, metformin inhibited tumor growth, which was negated by RBMS3 silencing. Our findings suggest that metformin promotes ferroptosis and inhibits ovarian cancer progression by upregulating RBMS3, offering a promising direction for clinical application in ovarian cancer treatment.