The role of metformin in extracellular matrix-based three-dimensional cell culture Models: A mini-review on therapeutic potentials

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Metformin, a widely used antidiabetic agent, exhibits pleiotropic effects extending beyond glycemic control, including the modulation of the extracellular matrix (ECM). Although traditional two-dimensional (2D) cell cultures have provided foundational insights, they inadequately replicate the complex tissue microenvironment in which metformin exerts its therapeutic actions. Emerging evidence underscores the pivotal role of ECM composition, stiffness, and cellular context in determining metformin's efficacy-particularly in cancer, fibrosis, and metabolic diseases. However, a comprehensive synthesis of its actions within physiologically relevant three-dimensional (3D) models remains lacking. This mini-review addresses this gap by systematically analyzing the interplay between metformin and the ECM in advanced 3D cell culture systems. We focus on metformin's ability to reprogram stromal cells, modulate mechanotransduction pathways (e.g., AMPK/mTOR), and influence cell-ECM dynamics within specific disease contexts. Furthermore, we discuss the integration of metformin-loaded biomaterials with 3D platforms, highlighting their dual function as drug delivery vehicles and active components of disease models. By synthesizing recent findings, this review emphasizes the bidirectional relationship between metformin and the ECM, positioning 3D culture models as indispensable tools for elucid

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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