Metformin in endometrial cancer from metabolic regulation to precision therapeutics

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with incidence rising in parallel with obesity, insulin resistance, and type 2 diabetes (T2DM). EC exhibits characteristic metabolic vulnerabilities, including hyperactive glycolysis, mitochondrial dysfunction, and PI3K/AKT/mTOR pathway activation, driven by unopposed estrogen stimulation and systemic metabolic dysregulation. Metformin, a first-line antidiabetic agent and mitochondrial complex I inhibitor, has emerged as a promising repurposed drug for EC prevention and treatment through dual mechanisms: direct tumor suppression via AMPK/mTOR, PI3K/Akt, Wnt/β-catenin, and endoplasmic reticulum stress pathways; and indirect metabolic microenvironment improvement via insulin sensitization, sex hormone-binding globulin upregulation, and immune microenvironment remodeling. This narrative review comprehensively summarizes available preclinical mechanistic insights and published clinical evidence across EC disease spectrum: chemoprevention in high-risk populations (obesity, PCOS), fertility-preserving treatment for early-stage disease, and combination strategies for advanced/recurrent EC. We synthesize existing data rather than adopting formal systematic review methodology with predefined database retrieval and PRISMA-compliant screening criteria. We critically analyze survival outcomes, response heterogeneity contingent upon diabetic status and molecular subtypes, and current bottlenecks in biomarker-guided patient selection. Furthermore, we propose translational strategies for precision application: LKB1/PTEN status-based patient stratification, innovative combinations with CDK4/6 inhibitors, mTOR inhibitors, and immune checkpoint inhibitors, and clinical pathway optimization. By bridging metabolic endocrinology and gynecologic oncology, the available data provide preliminary theoretical basis to explore future shift of metformin from empirical off-label reuse toward biomarker-guided individualized medication, which still needs large-scale prospective validation.