Hippo signaling in mechanobiology: Mechanical control of YAP/TAZ and their roles in disease

Mechanical forces are fundamental regulators of cell behavior, tissue architecture and disease. The Hippo–YAP/TAZ pathway has emerged as a key mechanosensitive system that integrates extracellular matrix stiffness, cytoskeletal tension, cell–cell contact, and shear stress into transcriptional responses. Mechanical regulation of Hippo signaling operates across multiple cellular scales—from membrane-associated scaffolds and cytoskeletal dynamics to nuclear transport, chromatin organization and enhancer activation—shaping proliferation, differentiation, regeneration and tissue repair. Dysregulation of this mechanotransductive axis contributes to fibrosis, cancer progression, vascular remodeling and metabolic disorders. Recent advances reveal that Hippo signaling is structurally organized through spatially confined signaling assemblies, providing a physical framework for coupling mechanical inputs to biochemical activation. These assemblies modulate MST1/2–LATS activity, influence YAP/TAZ nuclear localization and support the formation of transcriptionally active TEAD complexes. Mechanical cues, osmotic adaptation and metabolic states converge on these regulatory architectures, enabling cells to translate physical forces into sustained gene-expression programs. Viewing Hippo signaling as a mechanochemical system unifies diverse observations across physiology, disease and emerging structural biology. This framework highlights new therapeutic opportunities, including modulation of YAP/TAZ activity through targeting upstream mechanosensors, nuclear transport mechanisms or TEAD-associated regulatory complexes.