Metformin Induces Ferroptosis and Inhibits Malignant Progression in Diabetic Breast Cancer.

Diabetic breast cancer patients often experience poor prognosis. This study explores the therapeutic potential of metformin inducing ferroptosis across different breast cancer subtypes and examines its effect on prognosis, with a particular focus on diabetic patients. Ferroptosis and its relationship with prognosis and molecular subtypes were analyzed using data from the TCGA database. Clinical patient data were used to assess the impact of metformin on survival. Immunohistochemical staining was performed to evaluate the effect of metformin on GPX4 expression. In vitro experiments simulated diabetes using advanced glycation end-products, and ferroptosis was assessed by evaluating cell proliferation, migration, glutathione, malondialdehyde, and iron levels. TCGA analysis suggested that breast cancer patients with high ferroptosis-related risk scores may have a poorer prognosis. Luminal subtypes exhibited higher antioxidant capacity. Diabetic patients treated with metformin showed improved five-year survival (p = 0.0236) and reduced GPX4 expression (p = 0.0291). In vitro experiments demonstrated that metformin increased iron levels, reduced GSH, and enhanced lipid peroxidation. Exposure to advanced glycation end-products altered ferroptosis sensitivity, increasing susceptibility in MCF-7 cells while decreasing it in MDA-MB-231 cells. Metformin-induced ferroptosis may underlie its survival benefit in diabetic breast cancer patients. The differential ferroptosis sensitivity among breast cancer subtypes highlights the need for subtype-specific therapeutic strategies. The finding that the advanced glycation end-products differentially modulates this sensitivity provides a mechanistic basis for personalized therapeutic approaches targeting ferroptosis.