Extracellular matrix mechanics as a master regulator of mechanotransduction in tissue homeostasis and disease

The extracellular matrix (ECM) is a dynamic mechanochemical network that integrates biochemical ligands with physical cues—such as stiffness, viscoelasticity, topography, and confinement—to regulate cell fate and tissue homeostasis. Cells sense and transmit ECM-derived forces through integrin-based adhesions, the actin cytoskeleton, mechanosensitive ion channels, and the LINC complex, coupling cytoplasmic tension to nuclear mechanics, chromatin organization, and transcriptional programs. In this review, we summarize key mechanobiological principles across major ECM contexts and outline how “mechanical niches” are established and remodeled during development and repair. We highlight the adhesion–nucleus–chromatin axis and central transcriptional hubs, including YAP/TAZ-mediated mechanotransduction, that translate extracellular mechanics into gene expression and epigenetic memory. We further discuss how ECM stiffening, altered viscoelastic relaxation, and matrix compositional switching drive disease progression, with emphasis on fibrosis, cancer, and vascular pathologies. Finally, we survey emerging experimental platforms—tunable hydrogels, engineered and decellularized ECM, and quantitative 3D culture/organoid systems—that enable controlled perturbation of ECM mechanics and multiscale readouts. These approaches provide a foundation for improved biomarkers and therapeutic strategies aimed at normalizing pathological microenvironments and restoring tissue function.