Metformin in prostate cancer: a context-dependent antitumour strategy driven by metabolic vulnerability and signalling network
Abstract
Prostate cancer (PCa) is one of the most common malignant tumours in men and imposes a significant disease burden worldwide. Existing treatments have limitations such as drug resistance, and drug repurposing provides a new direction for drug management. Among the drugs explored, metformin has demonstrated certain preventive potential. Epidemiological evidence suggests that long-term use of metformin may be associated with reduced PCa incidence. This potential benefit is particularly evident in Asian and European populations. However, existing studies still exhibit heterogeneity, publication bias, and stage-specific variability. Its clinical efficacy varies by disease stage and individual patient characteristics: although it may reduce disease-specific mortality, evidence for consistent survival benefits remains limited and inconsistent. Notably, metformin possesses a favourable and controllable safety profile. Mechanistically, metformin exerts its antitumour effects through a coordinated network of metabolic and signalling pathways rather than a single dominant mechanism. In many prostate cancer contexts, inhibition of mitochondrial complex I likely represents a primary upstream event, leading to bioenergetic stress. This metabolic perturbation subsequently activates AMP-activated protein kinase (AMPK), suppresses mTOR signalling, and modulates androgen receptor (AR)-associated pathways. In parallel, metformin induces oxidative stress remodelling by increasing reactive…
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