SUMMARY

The extracellular matrix (ECM) provides structural support and mechanical cues that profoundly influence cellular behavior via nuclear mechanotransduction. This review discusses how ECM biophysical properties, including stiffness, topology, and spatial confinement, regulate nuclear mechanics and chromatin organization to determine cell fate across diverse pathophysiological contexts. We describe how mechanical signals propagate from the plasma membrane through cytoskeletal networks to modulate nuclear envelope tension, chromatin accessibility, and epigenetic landscapes. These matrix-driven nuclear changes orchestrate cellular responses in cancer progression, inflammation, fibrosis, stem cell differentiation, and age-related tissue dysfunction. Building on this mechanistic insight, we highlight emerging therapeutic strategies targeting the matrix-nucleus axis, such as tuning matrix properties to modulate chromatin accessibility, mechano-priming cells to enhance therapeutic outcomes, and targeting mechanosensitive molecules in the cytoskeletal-nuclear interface. Collectively, these approaches represent a promising paradigm leveraging mechanically induced epigenetic regulation and nuclear mechanobiology for disease treatment and tissue regeneration.

https://www.sciencedirect.com/science/article/pii/S2211124725009477