Targeting Piezo1/2 ion channels for modulation of the lymphatic system: mechanisms, applications, and therapeutic prospects.

In recent years, the role of mechanosensation in lymphatic system development, functional homeostasis, and disease progression has received increasing attention. As key mechanosensitive receptors in lymphatic endothelial cells, Piezo1/2 ion channels respond to biomechanical stimuli such as fluid shear stress and interstitial pressure, thereby regulating calcium influx and downstream signaling pathways. These channels play pivotal roles in physiological processes, including lymphatic network formation, valve development, and the maintenance of meningeal lymphatic function. This review systematically describes the structural features and dynamic mechanisms of Piezo1/2 channels, with a particular focus on their biological functions within the lymphatic system. Piezo1 integrates multiple signaling pathways, including the Orai1/Notch, ANGPT/TIE/FOXO1, and EPHB4/RASA1 signaling pathways, to regulate lymphatic sprouting, valve morphogenesis, and meningeal lymphatic development. Dysregulation of Piezo1 function has been demonstrated to be closely associated with congenital lymphoedema, tumor lymphatic metastasis, and neurological disorders such as hydrocephalus and craniosynostosis. In addition, the potential role of Piezo2 in the sensory impairments associated with lymphoedema warrants attention. With respect to therapeutic strategies, this review comprehensively summarizes approaches targeting Piezo1/2, including the development of small-molecule agonists/inhibitors, gene-editing technologies, physical modulation methods, and advanced drug delivery systems, as well as their research progress and clinical prospects. Despite persistent challenges such as insufficient tissue specificity and limited spatiotemporal precision, the integration of multiscale biomechanical models, organoid platforms, and multidisciplinary research strategies holds promise for translational breakthroughs in Piezo1/2 ion channel research, providing a new paradigm for precision therapy of lymphatic system-related diseases.