Aug 2026· Molecular Biomedicine· Vol 7· 0 citations· 291 references
Medicine
TL;DR
This review systematically summarizes the structure, mechanogating mechanisms, physiological and cellular functions of Piezo1, as well as its associations with human diseases.
Abstract
The Piezo1 channel is a mechanosensitive, non-selective cation channel that converts mechanical forces into electrochemical signals, playing pivotal roles in vertebrate physiology. Structurally, Piezo1 features a distinctive trimeric propeller structure that undergoes conformational changes in response to membrane tension, enabling mechanogating. Accordingly, Piezo1 is involved in a broad spectrum of physiological processes, including vascular development and homeostasis, bone and cartilage formation, skeletal muscle growth, neural development, sensory perception, immune regulation, and cellular volume regulation. Accumulating evidence indicates that mutations or dysregulation of Piezo1 are closely associated with a variety of human diseases, including genetic diseases, cardiovascular diseases, infectious diseases, autoimmune diseases, and cancer. Therefore, Piezo1 has emerged as a potential therapeutic target. Currently, the exploration of pharmacological modulators targeting Piezo1, as well as emerging approaches such as gene therapy, artificial intelligence (AI)-driven drug discovery, and advanced drug delivery systems, offer potential avenues for the development of Piezo1-targeted therapeutic strategies. However, these approaches still face significant challenges regarding specificity, in vivo targeting, and context-dependent effects. This review systematically summarizes the structure, mechanogating mechanisms, physiological and cellular functions of Piezo1, as well as its associations with human diseases. Based on this, the limitations of current Piezo1-targeted therapeutic strategies and their future developmental directions are highlighted, while the therapeutic potential of targeting Piezo1 is emphasized.
Mechanosensitive Piezo1 and Piezo2 channels convert mechanical forces into intracellular signals, playing essential roles in both physiological homeostasis and disease pathogenesis. This review synthesizes current evidence on their involvement in major neurological disorders, including stroke, Alzheimer's disease, traumatic brain injury, and glioma. Piezo1 primarily contributes to neuroinflammation, blood-brain barrier disruption, and tumor mechanosignaling, whereas Piezo2 dysfunction leads to sensory deficits, mechanical allodynia, and impaired proprioception. Notably, the functional consequences of Piezo activation are context-dependent: Piezo1 exacerbates ischemic brain damage but promotes amyloid-β clearance in Alzheimer's disease. Pharmacological modulators such as GsMTx4 and Yoda1 show promise in preclinical models, yet challenges remain regarding subtype selectivity and blood-brain barrier penetration. Targeting Piezo channels represents a promising therapeutic frontier, but success will require precise, cell-specific modulation based on disease stage and molecular context. This review highlights key pathogenic mechanisms, evaluates current pharmacological strategies, and outlines future directions for translating Piezo-targeted interventions into clinical practice.
Lu Zhao, Chao Wang, Yu-Dan Zhu et al.· Current opinion in pharmacol...· 0 citations
The mechanical cation channel Piezo1 has been confirmed as a key membrane mechanical protein that can convert physical forces into biological signals, serving as a molecular hub linking hemodynamic stimulation with thrombotic diseases. Studying mechanical sensitive channels in the cardiovascular system is helpful for understanding the working mechanism of these channels and providing new therapeutic targets for thrombotic diseases. This article systematically summarizes the expression and functional roles of the Piezo1 channel in cell types involved in thrombosis, including platelets, endothelial cells, red blood cells, immune cells, etc. This article also discusses the mechanical gating structural basis of Piezo1 and its activation mechanism and downstream signaling pathways in the thrombosis-related mechanical microenvironment. Based on the existing evidence, Piezo1 has significant pathological significance in the occurrence and development of thrombotic diseases, and targeting Piezo1 may provide new strategies for anti-thrombotic treatment. Future research needs to further clarify the differential regulatory mechanisms of the Piezo1 channel in different hemodynamic environments and evaluate its safety and efficacy as a drug target.
Han-Rong Dong, Yun-Lun Li, Wen-Qing Yang· International Journal of Mol...· 0 citations
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.
Rui-Ming Wen, Hai-Xia Wang, Weifeng Pan et al.· Biochemical Pharmacology· 0 citations
Mechanical forces are integral to musculoskeletal homeostasis and pathology. Piezo1 is a mechanosensitive ion channel widely expressed in bone, cartilage, muscle, and tendon. It converts mechanical stimuli (tension, compression, shear) into Ca2+ influx and downstream signals, regulating proliferation, differentiation, metabolism, inflammation, and apoptosis. This review summarizes Piezo1's structure, gating mechanisms, tissue expression, and functions in the musculoskeletal system, focusing on cartilage degeneration, subchondral bone remodeling, skeletal remodeling, muscle maintenance, and tendon adaptation. Under physiological conditions, Piezo1 contributes to tissue homeostasis; however, under abnormal or sustained loads, excessive Piezo1 activation can disrupt Ca2+ balance, amplify inflammation, promote apoptosis, and contribute to pathological remodeling in osteoarthritis, osteoporosis, muscle injury, and tendon degeneration. Preclinical strategies, including chemical agonists/inhibitors, traditional Chinese medicine components, gene-based approaches, and stem-cell-related interventions, have been explored in cell and animal models. Piezo1 is an important mechanosensitive regulator linking mechanical cues to musculoskeletal biology, although its tissue-specific roles, interactions with other mechanosensitive channels, and clinical translational value require further study.
Hong Zhao, Jun-Yang Huang, Ya-Yi Tan et al.· Bone Reports· 0 citations
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 signalling 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 signalling pathways, including the Orai1/Notch, ANGPT/TIE/FOXO1, and EPHB4/RASA1 signalling 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, tumour 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.
Jing-Shu Wu, Xin-Xian Meng, Cheng-Yao Han et al.· Burns & Trauma· 0 citations
Central nervous system (CNS) diseases are characterized by high rates of disability and mortality, and their pathological progression is generally accompanied by abnormal remodeling of the extracellular matrix (ECM) composition and mechanical properties. The mechanosensitive cation channel PIEZO1 is widely expressed in neurons, microglia, astrocytes, oligodendrocytes, and endothelial cells of the CNS. It can precisely sense mechanical signals such as ECM stiffness, viscoelasticity, shear stress, and matrix protein cross-linking, and convert them into intracellular calcium signals and downstream biochemical reactions, thereby mediating the mechanobiological crosstalk between the ECM and cells and playing a key role in physiological processes such as neurodevelopment, synaptic plasticity, blood–brain barrier (BBB) homeostasis, neuroimmune regulation, and cell fate determination. In diseases such as Alzheimer’s disease (AD), ischemic stroke (IS), and multiple sclerosis (MS), abnormal stiffening or remodeling of the ECM can lead to excessive activation of PIEZO1, which, by regulating pathways such as nuclear factor-kappa B (NF-κB), Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), calcium/calmodulin-dependent protein kinase II (CaMKII), and glutathione peroxidase 4 (GPX4), exacerbates neuroinflammation, BBB disruption, myelin destruction, neuronal ferroptosis, and defective axonal regeneration. This article systematically reviews the cellular expression profile of PIEZO1 in the CNS, the ECM-mediated activation mechanisms, and downstream signaling networks. It elucidates the regulatory role of the ECM-PIEZO1 axis in both the physiological functions and typical diseases of the CNS, aiming to provide a theoretical basis and new insights for mechanobiological research into the mechanisms and targeted therapies of CNS diseases.
Xiping Zhang, Yu-Chen Zhu, Si-Qi Song et al.· Frontiers in Neurology· 0 citations
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