Revisiting potential role of metformin in the circRNA-miRNA-mRNA axis: translational medicine perspectives in gastrointestinal cancer

Metformin, a widely prescribed antidiabetic drug with a well-established safety profile, has attracted increasing interest as a candidate for drug repurposing in oncology. Epidemiological, preclinical, and translational studies suggest that metformin exerts antitumor effects through both systemic metabolic regulation and direct modulation of intracellular signaling pathways, particularly the PI3K/AKT/mTOR axis. In parallel, circular RNAs (circRNAs) have emerged as key regulators of cancer biology, acting as microRNA sponges, transcriptional regulators, and, in some cases, templates for peptide translation. Increasing evidence implicates circRNA-miRNA-mRNA networks in gastrointestinal cancer initiation, progression, therapy resistance, and immune evasion. This review critically examines the role of metformin as a metabolic modulator of the circRNA-miRNA-mRNA regulatory axis in gastrointestinal cancers, focusing on gastric, colorectal, and hepatocellular carcinomas. We distinguish experimentally supported mechanisms from theoretical pathway-based intersections, discuss the translational potential of circRNAs as biomarkers, and highlight the current limitations and future research priorities. Collectively, the available data support a conceptual framework in which metformin indirectly reshapes oncogenic RNA networks via AMPK/mTOR signaling, providing a rationale for biomarker-driven clinical studies in precision gastrointestinal oncology.