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

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 elucidating context-dependent drug responses. We also identify key challenges, including the lack of standardized ECM-based systems and the underrepresentation of immune and vascular components, and propose future directions for translating these models into personalized therapeutic strategies. This work underscores the necessity of moving beyond conventional 2D paradigms to fully harness metformin's therapeutic potential through the adoption of 3D ECM-based systems.