YAP/TAZ signaling and ECM dynamics integrate mechanobiology with metabolic reprogramming across organ systems

The intricate link between physical forces and cellular metabolism, known as mechanobiology, is crucial for transcriptional, metabolic, and epigenetic adaptations. However, the precise mechanisms by which extracellular matrix (ECM) dynamics and mechanotransduction pathways orchestrate metabolic reprogramming in both healthy and diseased states remain largely undefined. Understanding this coordination is vital, as dysregulation contributes to conditions like cardiovascular remodeling, fibrosis, and metabolic disease. This review addresses this gap by proposing an integrative framework centered on the YAP/TAZ signaling axis.

This comprehensive review synthesized current literature to establish a focused mechanometabolic framework. It integrated findings across cardiovascular, skeletal, and endocrine systems, emphasizing the convergence of ECM remodeling, cytoskeletal tension, and force-dependent signaling pathways. The authors critically examined the role of the YAP/TAZ signaling axis as a central mechanosensitive transcriptional regulator. They also explored how aberrant mechanotransduction contributes to various pathologies and discussed emerging evidence linking viscoelasticity, mitochondrial dynamics, and immunometabolism to disease progression and therapeutic responses.

The review positions the YAP/TAZ signaling axis as a key mechanosensitive transcriptional regulator, acting downstream of integrin-focal adhesion kinase (FAK)-Src, RhoA/ROCK, actomyosin tension, and both Hippo-dependent and Hippo-independent signaling networks. This axis directly influences metabolic programs, including glycolysis, mitochondrial function, redox homeostasis, and anabolic biosynthesis. Key downstream targets identified include GLUT1, HK2, and PFKFB3, which are critical for glucose metabolism. Aberrant mechanotransduction, often involving dysregulated YAP/TAZ activity, was shown to contribute significantly to cardiovascular remodeling, endothelial dysfunction, and fibrosis. The review also highlighted the context-dependent roles of YAP/TAZ in mediating adaptive versus pathological responses. > In skeletal metabolism, the gut-bone axis was presented as a bidirectional mechanochemical network, where microbiota-derived metabolites, osteoimmune signaling, and biomechanical loading collectively regulate bone remodeling and systemic metabolism.