Mechanobiology-Driven Metabolic Reprogramming: Integrative Roles of YAP/TAZ Signaling and Extracellular Matrix...

Mechanobiology has emerged as a critical regulator of cellular metabolism, linking physical forces to transcriptional, metabolic, and epigenetic adaptations across multiple organ systems. However, the mechanisms by which extracellular matrix (ECM) dynamics and mechanotransduction pathways coordinate metabolic reprogramming in physiological and pathological conditions remain incompletely understood. This review provides a focused mechanometabolic framework integrating cardiovascular, skeletal, and endocrine systems through the convergence of ECM remodeling, cytoskeletal tension, and force-dependent signaling pathways. Central to this framework is the YAP/TAZ signaling axis, which functions as a mechanosensitive transcriptional regulator downstream of integrin-focal adhesion kinase (FAK)-Src, RhoA/ROCK, actomyosin tension, and Hippo-dependent and Hippo-independent signaling networks. These pathways regulate metabolic programs involving glycolysis, mitochondrial function, redox homeostasis, and anabolic biosynthesis through downstream targets including GLUT1, HK2, PFKFB3, and mitochondrial regulatory pathways. The review critically examines how aberrant mechanotransduction contributes to cardiovascular remodeling, endothelial dysfunction, fibrosis, and metabolic disease progression, while also discussing the context-dependent roles of YAP/TAZ signaling in adaptive versus pathological responses. In skeletal metabolism, the gut-bone axis is presented as a bidirectional mechanochemical network in which microbiota-derived metabolites, osteoimmune signaling, and biomechanical loading coordinately regulate bone remodeling and systemic metabolism. Furthermore, the review evaluates emerging evidence linking viscoelasticity, mitochondrial dynamics, and immunometabolism to disease progression and therapeutic responsiveness. Advances in mechanobiomaterials and regenerative strategies are also discussed, emphasizing their ability to modulate cellular energetics and mechanotransduction pathways to restore tissue homeostasis. Finally, current limitations in mechanobiology research, including model heterogeneity, tissue-specific mechanical responses, and translational barriers, are highlighted. Collectively, this review establishes mechanobiology as a systems-level regulator of metabolic reprogramming and underscores the therapeutic potential of targeting mechanometabolic pathways in human disease.