The Piezo1/YAP mechanotransduction axis: From mechanistic insights to therapeutic perspectives in disease.

Abstract

Cells and tissues are continuously exposed to mechanical cues from their surrounding microenvironment. Mechanobiology investigates how these cues are converted into intracellular biochemical and transcriptional responses. Piezo1, a mechanosensitive cation channel, mediates Ca2+ influx in response to changes in cell membrane tension. This Ca2⁺ signal can influence the activity and subcellular localization of Yes-associated protein (YAP) in a context-dependent manner, thereby contributing to physiological homeostasis and pathological progression. This review specifically focuses on the role of the Piezo1/YAP axis in regulating key physiological processes such as skeletal development, neural plasticity, macrophage polarization, epithelial homeostasis and barrier function, and cardiac development. Under pathological conditions, aberrant mechanical cues such as disturbed shear stress, matrix stiffening, and sustained mechanical overload can activate Piezo1-mediated Ca2⁺ influx and YAP-dependent transcriptional programs, thereby promoting endothelial inflammation, vascular remodeling, tumor cell proliferation, epithelial-mesenchymal transition, metastasis, and degenerative changes in skeletal tissues. Furthermore, this review evaluates emerging intervention strategies targeting the Piezo1/YAP axis, including small-molecule modulators and nanotechnology-based approaches. Although these strategies have shown promise in preclinical studies, their clinical translation remains at an early stage and is limited by challenges related to target specificity, bioavailability, tissue-selective delivery, dosage control, off-target mechanobiological effects, and long-term safety. Overall, this review aims to elucidate the current understanding of the Piezo1/YAP axis from mechanistic insights to therapeutic perspectives, while highlighting the need for further validation before clinical application.