Piezo1-mediated mechanotransduction and metabolic regulation in bone health: molecular mechanisms and implications for bone disorders

Bone continuously adapts to mechanical forces to maintain structural integrity, yet the molecular sensors that initiate this process have long remained undefined. The identification of the mechanosensitive ion channel Piezo1 has provided a pivotal molecular basis for understanding skeletal mechanotransduction. This review summarizes current advances in elucidating the unique structural features and force-gating mechanisms of Piezo1, and highlights its role as a central mechanoreceptor coordinating mechanical responses within bone tissue. We further delineate the multidimensional downstream signaling networks activated by Piezo1 and discuss the complex crosstalk among these pathways. The pathological consequences of Piezo1 dysregulation in major orthopedic disorders are examined, along with the therapeutic potential and challenges of targeting Piezo1 as a novel "mechanopharmacological" strategy. Collectively, this review provides an integrated framework for understanding the molecular foundations of bone mechanotransduction and identifies Piezo1 as a promising target for developing innovative treatments for orthopedic diseases.