Noninvasive biophysical modulations of Piezo ion channels

Abstract

Piezo channels are integral to numerous physiological functions: Piezo 1 modulates blood pressure through shear stress sensing and plays a role in cellular development and epigenetic processes. Conversely, Piezo 2 is implicated in sensory perceptions, including tactile sensation, balance, and nociception. Piezo channels are biophysical mechanosensitive ion channels that convert mechanical forces into electrical signals within cells. In this review, we investigate the recent advancements in the application of noninvasive biophysical techniques to modulate Piezo ion channels, thereby affecting diverse physiological functions. We also explore different electromechanical modulation methods for Piezo channels and discuss their significance. Furthermore, we emphasize various optical and magnetic techniques for modulating Piezo channels. Finally, we examine the potential applications of Piezo channel modulation for the treatment of neurodegenerative diseases, an area with significant potential to impact healthcare. The noninvasive activation of Piezo ion channels through mechanobiology holds significant potential for advancements in healthcare and for understanding and addressing neurodegenerative and degenerative diseases.

Introduction

In natural environments, a diverse array of organisms utilizes various physical stimuli—such as mechanical vibrations, acoustic waves, magnetic fields, electric currents, and light—to detect environmental cues. This capability facilitates essential physiological functions including auditory perception, vision, tactile sensation, pain recognition, and thermosensation. Mechanobiological transduction in epigenetics is essential across various cell types, impacting migration, proliferation, and differentiation by modulating gene expression without modifying the DNA sequence¹.

In 2010, Coste et al.² discovered a new family of mechanically activated cation channels in eukaryotes, known as Piezo ion channels, which were proposed to be the long-awaited mechanosensitive ion channels in mammals. Piezo channels rapidly respond to diverse forms of mechanical stimulation and convert them into biological signals that modulate various physiological processes. Over the past decade, significant progress has been made in leveraging the mechanical stimulation of Piezo channels to decode and manipulate biological systems^3–7. In this review, we explore recent progress in understanding Piezo channels, highlighting the fascinating history behind the Piezo channel principle and its important role in controlling various physiological functions. We also discuss exciting future possibilities in non-invasive sonogenetics and sonoepigenetics, opening new doors for innovative research⁸. Initially, we classify Piezo channel modulation methods into four main categories: mechanical, electrical, optical, and magnetic stimulation. Then, we explore the neurodegenerative disorders associated with Piezo channels in response to various mechanical stimuli. Finally, we outline potential directions for future mechanobiological research focused on Piezo channels.

Understanding the principles of the Piezo channel: a historical overview

The conceptual foundation for mechanotransduction predates the discovery of Piezo channels. As early as the 1950s, Katz et al.⁹ hypothesized the existence of a “piezo-electric substance” within muscle spindles, based on electrophysiological recordings showing that mechanical deformation of muscle tissue could generate measurable bioelectric responses, as shown in Fig. 1a. This notion was further strengthened by later findings demonstrating intrinsic piezoelectric properties in various biological materials—including collagen, bone, and connective tissues—suggesting that living systems can inherently convert mechanical forces into electrical signals^10–12. In 1987, Martinac et al. first functionally identified pressure-sensitive ion channels in Escherichia coli using patch-clamp techniques¹³, as shown in Fig. 1b. Subsequently, these channels were further characterized as MscS and MscL through molecular cloning and reconstitution in the 1990s^14–16. These foundational discoveries collectively established the mechanobiological framework that ultimately enabled the identification of Piezo channels in mammals. Subsequently, researchers have investigated the structural composition of these channels and their functions, such as tactile perception and proprioception, as well as their relationship to various physiological processes and health conditions in humans.

Fig. 1. The history of understanding the Piezo channel principle over time.

It highlights how this knowledge has progressed, shedding light on the development of this important scientific concept. a Existence of a “piezo-electric substance” within muscle spindles in the 1950s. b Identification of bacterial mechanosensitive channels in the 1980s. c Architecture of Piezo channel as understood in 2015. d Modularization mechanism identified in 2016. e Membrane dome mechanism discovered in 2017. f Lever-like transduction mechanism developed in 2018. g Dual-gating mechanism introduced in 2019. h Plug-and-latch mechanism identified in 2020. i Curvature sensing mechanism elucidated in 2020. Each panel highlights significant advancements and conceptual breakthroughs in the study of Piezo channels over the years

Piezo channels, recognized for their specific functions in the cell membrane, are essential in mechanotransduction in biological systems, converting mechanical forces into biological signals¹, as shown in Fig. 2. The name of Piezo is derived from the Greek word piezein, meaning ‘to press.’ Piezo channels are mechanosensitive ion channels that transduce mechanical force into biological signals through ion permeation, rather than generating a voltage potential through the direct deformation of a piezoelectric material. Piezo channels consist of about 2500 amino acids and have multiple transmembrane (TM) regions². Cryo-electron microscopy studies have shown that Piezo channels have a three-bladed, propeller-like structure featuring a central core, three peripheral blade-like parts on the outside, three long beams on the inside, and TM regions that connect these parts^3–7. Additional research confirms that Piezo channels, known as pore-forming ion channels, can be directly activated by membrane stretching^17,18. Notably, while direct activation by membrane stretch has been convincingly demonstrated for Piezo1, such a mechanism has yet to be definitively proven for Piezo2.

Fig. 2. Schematic illustration of the physical and protein structures of Piezo ion channels, demonstrating how mechanical stimulation is converted into electrical signals by the ion gradient across the cell membrane.

a–d Mechanical stimulation leads to conformational changes in Piezo channels, increasing their open probability and enabling rapid ion flux. Piezo ion channels operate within the biophysical principles governing ion-permeable membrane proteins. Ion channels serve as selective conduits that allow charged particles such as Na⁺, K⁺, Ca²⁺, and Cl⁻ to flow. e, f This flux alters the transmembrane potential (Vₘ), generating fast electrical signals that propagate within cells and across neural circuits. The membrane potential can be approximated by the Goldman–Hodgkin–Katz (GHK) equation when multiple ion species contribute, whereas voltage dynamics over time are captured by the Hodgkin–Huxley (H–H) formalism. The H–H model treats ion channels as variable conductances (g_i) regulated by gating variables sensitive to mechanical force in the case of Piezo channels. In this framework, mechanically activated Piezo currents depolarize membranes by permitting cation influx, thereby converting physical forces into bioelectronic signals essential for cellular mechanotransduction

Central component

The central structure comprises the C-terminal extracellular domains (CEDs), transmembrane inner helices (IHs) and outer helices (OHs), and intracellular C-terminal domains (CTDs)¹⁹, as shown in Fig. 1c. The assembly of three CEDs forms an extracellular cap²⁰. At the center, the TM37 and TM38 regions correspond to the IHs and OHs, respectively, and collectively constitute the transmembrane pore of the central cap¹. The anchor connects the OH-IH pair to the CTD plane²¹. The central component facilitates the function of the pore-forming ion channel, ensuring efficient ion conduction and selective cation permeability over anions. The functional roles of these structures in gating and ion conduction are largely inferred from static conformations. Although cryo-EM provides essential architectural data²², capturing their dynamic modulation under diverse pathological conditions remains a challenge. Specifically, the precise impact of the CEDs and CTD on pore gating requires more direct verification through high-resolution dynamic electrophysiology and targeted in vivo mutational studies.

Three peripheral blade-like structures

The three peripheral blade-like structures consist of nine transmembrane helical units (THUs), each made up of four TM regions. The peripheral THU1-3 remains unresolved in structural analysis. The peripheral THU4-6 and proximal THU7-9 domains align at a 100-degree angle. TM13, TM17, TM21, TM25, and TM29 regions form L15-16 and L19-20, shaping the helical structures⁴. These features are well suited to influence local membrane curvature and aid mechanotransduction²³. The highly curved membrane indicates that Piezo channels are affected by cellular membrane curvature and tension¹⁸. Structural and computational models hypothesize that these extended blades dictate mechanosensitivity by coupling with membrane curvature²⁴. However, their functional execution in varied physiological processes, such as adapting to different native lipid environments, remains speculative, which means their specific contributions to force transmission and disease-associated variants are primarily derived from indirect inference.

Beams

Three beam-like structures, each 90 Å in length, are positioned on the intracellular side of the membrane, supporting the transmembrane structures²⁵. The three long beams physically connect the blade-like structures to the central component. The beam functions like a lever, with residues L1342 and L1345 in the beam serving as a pivot²⁶. The beam connects the distal blades to the central component, which converts mechanical force into ionic conduction^3,27. The hypothesis that beams function as force-amplifying levers relies heavily on computational predictions and structural modeling²⁸. The direct influence of beams on channel gating and their interaction with cell membrane mechanics still require more robust experimental confirmation.

Modularization mechanism (2016)

Piezo channels consist of a central ion-conducting pore module and three external mechanotransduction modules²⁹, each serving distinct functions, as shown in Fig. 1d. The pore module includes the CEDs, a transmembrane pore, and an intracellular CTD. The mechanotransduction modules comprise long beam-like structures, peripheral blades that induce plasma membrane curvature, and an anchor that maintains structural integrity³⁰. The three external mechanotransduction modules transmit mechanical force to open the central ion-conducting pore, facilitating ionic conduction. This model, which describes the Piezo structure as having a central pore and three mechanotransduction modules, is well supported by high-resolution data, including single-particle cryo-EM, X-ray crystallography, and live-cell immunostaining²². But it lacks direct experimental validation regarding the exact pathway through which membrane forces are transmitted, as shown in Table 1.

Table 1.

A comparison table of different mechanotransduction models

Models	Main methods	Key data	Limitations	Ref.
Modularization mechanism	• Cryo-EM • X-ray crystallography • Live-cell immunostaining	• Length: ~2100–4700 amino acids across Piezo homologs • Predicted TM segments: 24–36 TM domains • Pore module: 2189–2547 amino acids • Non-pore mechanotransduction module: Residues 1–2190	• Lack of experimental validation of membrane force transmission.	22,29
Membrane dome mechanism	• Free energy calculations	• Area change: ~120 nm², stabilizes open state by ~42 kBT at low tension • Bending energy: Bending membrane costs ~150 kBT	• Simplification of membrane dynamics. • Exclusion of lipid and external factor effects. • Need for additional experimental verification.	5
Lever-like mechanotransduction mechanism	• Cryo-EM • Cell-attached electrophysiology	• Rotational spacing (Blades): 100°–140° between adjacent blades • Beam length: ~90 Å • Beam positioning angle: ~30° relative to the membrane	• Simplifies mechanical transmission. • Lack of consideration of actual molecular interactions. • Lack of diverse validation.	22
Dual-gating mechanism	• Cryo-EM • Cell-attached electrophysiology	• Upper constriction site: ~1 Å • Lower narrow strait: ~10 Å	• Unverified dynamic regulation of the cap and plug.	7
Plug-and-latch mechanism	• Cryo-EM • Cell-attached electrophysiology • Live-cell immunostaining	• Lateral plug: Residues 1396–1405 • Latch: Residues 1406–1420	• Lack of direct experimental evidence of coordinated gating under physiological conditions.	34
Curvature sensing mechanism	• Cryo-EM • Free energy calculations	• Membrane area expansion: ~300 nm2 • Experimentally measured tension of half-maximal activation: ~1.4 pN nm−1	• Insufficient experimental data to confirm curvature-channel opening relationship. • Lack of data in complex physiological environments.	24
Filament-based mechanisms	• Cell-attached electrophysiology • Cytoskeleton-interaction	• Tension of half-maximal activation: • ~1.4 mN m−1 in intact cell membranes • ~3.4 mN m−1 in artificial lipid bilayers • ~4.5 mN m−1 in the lack of actin cytoskeleton	• Incomplete understanding of interactions between Piezo and the cytoskeleton. • Lack of more experimental data.	37

Membrane dome mechanism (2017)

Piezo channels, characterized by their trimeric propeller configuration, deform membranes into a dome-like structure, which is essential for their mechanotransduction process^5,31,32, as shown in Fig. 1e. When the dome is flattened by tension, the system’s energy increases, as calculated by the available free energy. Subsequently, the relative energy difference facilitates channel opening^4,7, clarifying the sensitive mechanical gating of Piezo channels that possess a cation-selective pore. This model explains Piezo activation via membrane deformation, which relies on free-energy calculations and computational hypotheses⁵. It requires further experimental verification and currently overlooks the complex influence of diverse lipid compositions and external mechanical factors, as shown in Table 1.

Lever-like mechanotransduction mechanism (2018)

Curved blades, equipped with transmembrane helical units, detect mechanical forces, while the beam, featuring pivotal residues Ll1342 and Ll1345, functions as a lever-like apparatus⁴ as shown in Fig. 1f. The lever-like beam couples the blades to the central pore and amplifies the force, opening the central pore and facilitating action flow². This lever efficiently translates large blade movements into small changes in pore opening, facilitating selective cation permeation due to the pivot’s proximity to the pore. This model proposes that the beam acts as a force-amplifying lever, which is a concept extrapolated from cell-attached electrophysiology combined with cryo-EM structural data²⁸. It oversimplifies the mechanical transmission and lacks diverse validation of actual molecular interactions, as shown in Table 1.

Dual-gating mechanism (2019)

Piezo channels exhibit a dual-gating mechanism, with a transmembrane gate regulated by an extracellular cap and lateral plug gates controlled by an intramolecular blade-beam structure⁷, as shown in Fig. 1g. The movement and constriction sites of the cap domain control pore opening, providing evidence of dual gating. This configuration enables precise control of ion flow modulated by mechanical stimulation³³. Piezo channels utilize the intracellular fenestrations and lateral portals for ion conduction within the cell. This dual-gating system suggests the potential for modality-specific responses to mechanical inputs, intricate regulation, and functional diversity in Piezo channels. This model describes Piezo gating via an extracellular cap and lateral plug. Its structural basis is strongly supported by high-resolution cryo-EM data⁷. But the dynamic regulation and the physical movement of the cap and plug during channel gating remain experimentally unverified, as shown in Table 1.

Plug-and-latch mechanism (2020)

Piezo channels physically and coordinately gate the lateral ion-conducting portals by unplugging the plug gates through the peripheral blade-beam apparatus^34,35, as shown in Fig. 1h. Tension-induced asymmetric conformational changes in the three sets of peripheral blade-beam apparatuses converge onto the central axis and evenly engage with the three lateral plug gates to facilitate coordinated gating²⁰. This model suggests peripheral blades unlock the plug to gate ion flow, which is supported by structural (cryo-EM) and functional (cell-attached electrophysiology, immunostaining) data³⁴. There is still a lack of direct experimental evidence demonstrating this coordinated gating behavior under true physiological conditions, as shown in Table 1.

Curvature sensing mechanism (2022)

The structural transition of Piezo channels from curved to flattened configurations significantly affects their dynamics within lipid membranes²⁴, as shown in Fig. 1i. This piezo-membrane system undergoes an in-plane membrane area expansion of approximately 300 nm², corresponding to changes in lateral tension and the free energy required to open the channel. Transitioning from the curved to the flat state involves a force of approximately 92 pN, accompanied by a work of roughly 570 pN nm and the half-maximal tension of 1.9 pN nm^{−1 31,36}, closely matching the measured Piezo activation value of 1.4 pN nm⁻¹. This model highlights the role of membrane curvature in Piezo activation, based on cryo-EM and free-energy calculations²⁴. It lacks sufficient experimental data to definitively link dynamic curvature changes directly to channel opening within complex, native physiological membrane environments, as shown in Table 1.

Filament- and ECM-based mechanisms (2022)

Beyond their intrinsic sensitivity to membrane tension, Piezo channel gating is also significantly modulated by the cytoskeleton and the extracellular matrix (ECM). Piezo channels are biochemically and functionally tethered to the actin cytoskeleton via the cadherin-β-catenin mechanotransduction complex, which is pivotal in regulating their gating behavior³⁷. Disruption of this mechanical linkage impairs Piezo-mediated responses, indicating that cytoskeletal components directly modulate or facilitate channel function. Furthermore, Piezo activation by traction forces regulates cellular differentiation in response to substrate stiffness in neural stem cells, underscoring the channel’s responsiveness to ECM-derived cues³⁸. Substrate properties such as roughness and stiffness tune Piezo activity, with cellular contractility often serving as a prerequisite for channel sensitization³⁹. Additionally, it has been shown that forces generated by the cytoskeleton or ECM can regulate the sensitivity of Piezo to mechanical stimuli, further highlighting the importance of cytoskeletal interactions in the mechanotransduction process⁴⁰. These findings suggest that Piezo channels integrate forces from both the lipid bilayer and the filament network to achieve precise mechanosensitivity. This speculative model hypothesizes that cytoskeletal or ECM forces modulate Piezo gating, based on initial cell-attached electrophysiology and cytoskeleton-interaction studies³⁷. The precise physical interactions between Piezo channels and the cytoskeleton remain poorly understood and currently lack definitive experimental confirmation, as shown in Table 1.

The mechanistic models of Piezo channels should be viewed as complementary rather than mutually exclusive, as they describe overlapping, multi-scale aspects of mechanotransduction. The modularization mechanism provides the foundational structural framework comprising 2100–4700 amino acids and 24–36 transmembrane domains upon which other functional models rely²⁹. Building upon this, the membrane dome mechanism describes 120 nm² area changes and 42 k_BT stabilization at low tension⁵, which operates in tandem with the lever-like mechanotransduction model involving rotational spacing between blades and a beam length of 80 Ų². Furthermore, the dual-gating mechanism defines the specific pore-level consequences, such as the radii of the top (1 Å) and bottom (10 Å) vestibule⁷. The curvature sensing and filament-based mechanisms integrate these intrinsic properties into physiological contexts, such as sensitivity to dynamic membrane tension and ECM interactions^24,37. Collectively, these models converge to provide an integrative understanding of Piezo-mediated mechanosensation.

Several small-molecule activators of Piezo channels have been identified, such as Yoda1 and Jedi1/2^{25,35,41–43}. Yoda1 is a hydrophobic agonist that inserts itself into the Piezo1 blade structure, thereby lowering the mechanical threshold required for activation³⁵. In contrast, Jedi1 and Jedi2 are hydrophilic molecules that trigger Piezo1 activation by binding to the extracellular domain of the blade structure and exploiting key mechanotransduction points within the bundle^25,43. These molecules provide a powerful noninvasive toolkit for modulating Piezo activity without direct physical stress.

In addition to small-molecule regulation, recent structural and functional studies have identified MyoD-family inhibitor proteins (MDFI and MDFIC) as auxiliary subunits of Piezo channels⁴⁴. These subunits interact with the channel’s pore module and modulate its gating and inactivation kinetics, particularly slowing inactivation rates, thereby contributing to the diverse mechanical sensitivities observed across different cell types. Furthermore, the recent discovery of MDFIC2 has expanded this family of auxiliary subunits⁴⁵. MDFIC2 modulates Piezo channel gating by slowing channel kinetics and shifting mechanical sensitivity toward higher force thresholds expressed in a subset of nociceptive sensory neurons.

Mechanobiological stimulation of Piezo channels

We investigate various electromechanical modulation techniques targeting Piezo channels. Low-frequency mechanical stimuli and high-frequency acoustic stimulation can emulate touch sensation, simultaneously activating Piezo channels and initiating molecular signaling cascades. This could impact both local tissue responses and cerebral function^2,46. Various vibrational and energetic modalities can activate Piezo channels, including compression, shear, stretching, and auditory stimuli^47–49. Vibration-induced endothelial shear stress can trigger Piezo channels, facilitating the formation and repair of blood vessels and nerves. Vibrotactile feedback can stimulate the motor cortex and modulate sensory signals in the dorsal horn and ascending arousal system through Piezo channels. The mechanisms underlying vibration response can be categorized into three main areas: hemodynamic, neurological, and musculoskeletal effects⁵⁰. Hemodynamic effects involve the stimulation of endothelial cells through shear and pressure. Neurological effects include activation of protein kinases and neural stimulation. Musculoskeletal effects comprise the muscle stretch reflex and osseous stimulation.

Hemodynamic effects

Vibration induces endothelial cell stimulation, releasing nitric oxide (NO) and adrenomedullin. This stimulation triggers endothelial cell remodeling via calcium-mediated pathways activated by Piezo channels^51,52. Elevated blood flow, whether due to physical exercise or vascular disease, increases shear rate, facilitating the synthesis of endothelial NO, which induces vasodilation by phosphorylating AKT and endothelial nitric oxide synthase (eNOS), as shown in Fig. 3a. Subsequently, NO regulates blood flow and vascular tone by activating guanylate cyclase (sGC) and phosphorylating extracellular signal-regulated kinase (ERK1/2)^53,54. Elevated blood pressure activates Piezo channels, releasing ADM and ATP and activating Gs-coupled receptors, which enhance NO synthase through the PKA-mediated pathways, thereby regulating blood pressure⁵⁵, as shown in Fig. 3a. Thus, hemodynamic effects can activate Piezo channels in endothelial cells, mediated by shear rate and pressure.

Fig. 3. Mechanobiological stimulation of Piezo channels.

The mechanisms that respond to sound waves are categorized into three main areas: hemodynamic, neurological, and musculoskeletal effects. a Hemodynamic effects: ultrasound induces endothelial shear stress, activating Piezo channels and triggering subsequent biological responses. b Neurological effects: vibration stimulates Piezo channels, promoting neurite outgrowth and neuronal differentiation through protein kinase activation and nerve stimulation. c Musculoskeletal effects: vibration triggers the muscle stretch reflex and osteocyte response, enhancing tendon stiffness and muscle hypertrophy. Acoustic stimulation of Piezo channels produces three primary effects: mechanical, cavitation, and thermal effects. d Mechanical effect: acoustic waves exert mechanical forces, activating Piezo channels via membrane deformation and shear stress. e Cavitation effect: ultrasound-induced bubbles generate microjets and shear stress through inertial and stable cavitation, facilitating ion exchange and Piezo channel activation. f Thermal effect: ultrasound absorption raises the local temperature, deforming Piezo channels and modulating cellular functions

Neurological effects

Mechanical vibration has significant neurological effects by stimulating Piezo channels. This stimulates protein kinases and nerve stimulation, facilitating neurite outgrowth and neuronal differentiation. Piezo channels are essential for axon growth, and their knockdown leads to abnormal growth and pathfinding errors⁵⁶.

In the context of protein kinases, axon growth during peripheral nerve repair requires the formation of growth cones, which are mediated by these kinases. Mechanical vibration induces calcium influx into the axoplasm, triggering a depolarizing wave from the axon to the soma and leading to gene expression within the neuron^57,58. The subsequent accumulation of calcium induces calpain-dependent cell membrane resealing through calcium-regulated proteins, facilitating growth cone formation⁵⁹, as shown in Fig. 3b. In Xenopus retinal ganglion cell models, increased brain stiffness has been shown to enhance Piezo-mediated axon growth, suggesting that extracellular forces and mechanical stimulation within the growth cone contribute to guiding axon growth along regions of tension^60,61.

Regarding nerve stimulation, vibration applied to Piezo channels can induce neurons to produce calcium ion transients, which are transformed into specific firing patterns⁶². Vibration is widely used to alleviate pain in orthopedics, low back pain, physiotherapy, cosmetic procedures, orthodontic work, and orofacial pain⁶³. Pain signals are transmitted to the dorsal horn via small-diameter afferent A-delta and C fibers. These signals can be modulated by large-diameter A-alpha and A-beta fibers, with vibration potentially inhibiting the transmission of pain signals^64,65, as shown in Fig. 3b. Salter et al. investigated neuronal responses to vibration and found that frequencies below 80 Hz contribute to analgesia⁶⁶. Xu et al.⁶⁷ discovered that various acupoints exhibit optimal responses to different sound frequencies during vibration stimulation.

Musculoskeletal effects

The physiological effects of vibration on muscles include the activation of the muscle stretch reflex and eliciting responses from osteocytes. In the muscle stretch reflex context, shear stress on tendon cells activates Piezo channels, triggering calcium influx and upregulating collagen crosslinking. This process increases tendon stiffness, potentially enhancing jumping performance⁴⁹. Furthermore, these stretches cause involuntary muscle contractions as a reflex to maintain muscle length⁶⁸. Low-frequency vibration can induce thousands of such contractions within minutes. The Akt/mTOR/p70S6K signaling pathway is crucial for muscle hypertrophy and the inhibition of atrophy; vibration stimulation enhances this pathway during mechanical loading and muscle injury⁶⁹, as shown in Fig. 3c. Studies have shown that Akt levels increase in response to muscle contractile activity and mechanical tension⁷⁰.

Regarding osteocyte responses, lower-frequency vibrations (<10 Hz) induce fluid flow within cells, resulting in calcium oscillations due to the increased cell deformability at these frequencies⁷¹, as shown in Fig. 3c. At higher frequencies, fluid flow is attenuated, and the nucleus becomes the primary target of vibration-induced cellular effects. Vibration within the 10–100 Hz frequency range can stimulate bone growth by doubling bone formation rates and mitigating osteoporosis⁷². Bacabac et al. investigated the impact of vibration on osteoblast precursor cells across frequencies from 5 to 100 Hz. They found that NO release positively correlated with frequency, whereas prostaglandin E2 (PGE2) release negatively associated with frequency⁷³. In vitro studies have shown that NO promotes osteoclast migration, while PGE2 stimulates osteoclast differentiation⁷⁴. Acoustic waves are widely studied as a critical form of stimulation. They generate mechanical stimulation, which elicits electrical responses in Piezo channels via three main mechanisms: mechanical, cavitation, and thermal effects.

Mechanical effect

Acoustic waves can directly apply mechanical forces to cells, activating Piezo channels via acoustic streaming⁷⁵, as shown in Fig. 3d. Membrane expansions and contractions activate Piezo channels, leading to calcium influx. Shear stress induced by acoustic waves can influence Piezo channels^76,77. Guo et al. developed a platform for producing acoustic streaming, controlling cell deformation, and analyzing the resulting mechanical and electrical responses⁷⁸. They investigated the ion permeability of the cell membrane during deformation induced by acoustic waves. The membrane stretches under negative acoustic pressure and retracts under positive acoustic pressure during the periodic variations in acoustic pressure. Krasovitski et al. proposed a bilayer membrane (BLM) model. This model facilitates the conversion of millimeter-wavelength oscillatory acoustic waves into cellular deformations at the nanometer or micrometer scale, activating mechanosensitive proteins and enhancing membrane permeability⁷⁹. Vasan et al. observed the dynamics of cell membranes using high-speed digital holographic microscopy. Under acoustic wave stimulation, a 150 nm deflection was observed in the membranes of neurons and fibroblasts, and the changes in membrane voltage were predicted⁸⁰.

Cavitation effect

The cavitation effect occurs when ultrasound induces particles, such as bubbles, to form microjets or shockwaves that exert mechanical forces on cells, as shown in Fig. 3e. Shear stress induced by cavitation applies force to activate Piezo channels and facilitate ion exchange. Inertial cavitation occurs at sufficiently high acoustic pressures, causing bubbles to collapse and generate microjets. Yuan et al. investigated the nonuniform deformation of membranes induced by inertial cavitation and analyzed the resulting mechanical forces on the membranes⁸¹. Li et al. explored the mechanism of calcium ion influx induced by inertial cavitation in a single HeLa cell⁸². They observed two types of calcium ion influx, induced by cell membrane deformation under various shear stresses. Shen et al. incubated the microbubbles to target Piezo channels in nerve cells⁸³. Acoustic stimulation triggers the opening of Piezo channels, allowing extracellular calcium to flow into the cells. Stable cavitation occurs at lower acoustic pressures, causing bubbles to oscillate reciprocally and induce microstreaming. Helfield et al. reported that stable cavitation of bubbles induced by ultrasound causes them to oscillate and exert shear stress on cells⁸⁴. They discovered a shear stress threshold induced by bubble oscillation. This kPa-level threshold increases the electric permeability of membranes. The shear stress threshold exhibits an inverse square root relationship with the number of oscillation cycles and an approximately linear relationship with frequency.

Thermal effect

Ultrasound absorption can elevate the temperature surrounding cells in biological tissue⁷⁵, as shown in Fig. 3f. Significant temperature increases can result from inertial cavitation. Nonlinear acoustic radiation from stable cavitation can also lead to immediate heating^85,86 in the surroundings. Exceeding the normal physiological range can deform the Piezo channel structure and disrupt cellular function^87,88. Under mild heating, the thermal effect can serve as a remote trigger for Piezo channels, enabling precise, on-demand, spatiotemporal, and dosage-controlled control to minimize harmful side effects⁸⁹. However, some studies suggested that the thermal effect is typically negligible in biomedical applications. The American Institute of Ultrasound in Medicine (AIUM) has established maximum ultrasound parameters for in vivo experiments on mammals⁹⁰ to address safety concerns. The maximum intensity for unfocused ultrasound is less than 100 mW/cm², and the maximum exposure duration is less than 500 s. For focused ultrasound (FUS), the limits are set at an intensity of less than 1 W/cm² and an exposure duration of less than 50 s to mitigate overheating risks.

Electrical stimulation of Piezo channels

Piezo channels exhibit distinctive responses to various forms of electrical stimulation. Electrical stimulation influencing Piezo channels can be categorized into three principal types: membrane potential directly regulates channel activity; particle-mediated stimulation by altering the membrane potential or the configuration of membrane receptors; and direct electric field stimulation, where external electric fields modify the transmembrane potential or tension to regulate the channel’s opening and closing. Each of these mechanisms provides unique insights into the understanding and manipulation of Piezo channel functions across diverse biological and medical disciplines.

Direct electrical/voltage gating

Mechanosensitive Piezo channels are evolutionarily conserved proteins. Both mammalian stretch-activated potassium channels⁹¹ and bacterial stretch-activated channels exhibit potential sensitivity⁹². However, the role of membrane potential in modulating Piezo channels remains insufficiently clarified. Recent studies have made significant advances in elucidating the mechanisms of membrane potential in mechanosensitive Piezo channels. Traditionally known for their mechanosensitivity, Piezo channels also respond to membrane potential, further augmenting their functional complexity. Potential fluctuations can induce conformational changes in Piezo channel residues, thereby activating the channel, as shown in Fig. 4a. Membrane potential sensitivity acts as a physiological tuner for Piezo channels, and alterations in membrane potential can significantly shift the channel’s mechanical activation threshold, thereby governing ion influx and downstream signaling in excitable cells. Moroni et al.⁹³ demonstrated that mutations associated with xerocytosis can enable Piezo channels to function in an electrical mode. At positive potential, the probability of Piezo channel opening increases, suggesting that elevated potentials facilitate channel activation. Subsequently, the outgoing ion flow is sufficient to induce a slow conformational change⁹⁴, potentially opening the inactivation gate and resetting the channel dynamics, as shown in Fig. 4a. These findings demonstrate that Piezo channels respond not only to direct mechanical stimuli but also adapt to membrane potential changes, which are critical for maintaining normal physiological function in multicellular organisms. Furthermore, Kaestner et al.⁹⁵ investigated how the membrane potential in red blood cells regulates cell volume in narrow capillaries. The previously identified non-selective potential-dependent cation channels in red blood cells are now recognized as Piezo channels. This capability suggests an evolutionarily conserved function of Piezo channels, demonstrating dual modulation by mechanical stimulation and potential changes to adapt to cellular environments. While the role of potential sensitivity in Piezo channels has been discussed, its full implications for cellular physiology remain underexplored. In particular, the exact mechanism by which membrane potential influences Piezo channel gating requires further experimental validation across diverse cell types and tissues. The ability of Piezo channels to respond to both mechanical and electrical stimuli emphasizes their integral role in cellular physiology and highlights their potential as therapeutic targets for various diseases. It should be clarified that Piezo channels do not meet the formal definition of piezoelectricity. Instead, they function as molecular transducers that respond to mechanical stimuli via conformational changes, facilitating mechanosensation rather than exhibiting intrinsic piezoelectric properties.

Fig. 4. Electric stimulation of Piezo channels.

a Potential-gating induces a gradual conformational shift that activates mechanosensitive Piezo channels. b Focused ultrasound induces nanoparticles to generate currents that remotely stimulate Piezo channels, demonstrating the potential for noninvasive therapeutic applications. c Redistribution of charged components in the membrane induces tension, stimulating Piezo channels when subjected to an external electric field

Piezoelectric particle stimulation

Nanoparticles can generate electrical currents to alter the membrane potential or the configuration of membrane receptors to remotely stimulate Piezo channels^96,97, as shown in Fig. 4b. These nanoparticles are categorized into inorganic and organic dielectric compounds, both of which can be electrically polarized upon mechanical stimulation⁹⁸. Among inorganic compounds, zinc oxide (ZnO) represents a nonferroelectric piezoelectric material, whereas barium titanate (BaTiO₃) and lead zirconate titanate (PZT) exemplify typical ferroelectric materials. Among organic materials, poly(vinylidene fluoride) (PVDF) is a common synthetic polymer and is often copolymerized with trifluoroethylene (TrFE) to form P(VDF-TrFE), thereby optimizing crystallinity. Kim et al.⁹⁹ designed piezoelectric nanoparticles for delivery into the brain parenchyma, where they induced membrane potential changes to stimulate dopamine release from dopaminergic neuron-like cells, as shown in Fig. 4b. Zhu et al. observed a maximum potential of 0.45 V in a cubic barium titanate nanocrystal under high acoustic pressure, which can activate Piezo channels¹⁰⁰. Li et al. designed a composite of piezoelectric PVDF and ZnO particles within a porous ferroelectric structure to activate the channels to observe calcium influx¹⁰¹.

However, the physiological relevance of particle-mediated stimulation in in vivo systems is still under investigation. A primary challenge is the biocompatibility and long-term safety of nanoparticles, particularly regarding their accumulation and potential tissue toxicity¹⁰². Although in vitro studies offer valuable insights into Piezo channel activation, translating these findings to in vivo systems presents profound challenges. In vitro models fundamentally lack the complex, dynamic biomechanical landscape of living organisms, such as 3D extracellular matrix confinement, continuous interstitial flow, and systemic cytoskeletal coupling⁷³. The translation of these findings to in vivo systems is critical for understanding how Piezo channels contribute to physiological processes. Consequently, there is an urgent need for comprehensive in vivo studies to assess the generalizability of existing in vitro findings.

Electric field

The electric field influences Piezo channels responding to changes in membrane tension by altering the transmembrane potential, which affects cell signaling and behavior, as shown in Fig. 4c. Applying an electric field redistributes electrical charges across the cell membrane, effectively altering it and directly influencing the function and conformation of Piezo channels, modulating their opening and closing to regulate calcium flow in response to changes in membrane tension¹⁰³. Specific electrical stimulation parameters, such as field strength and frequency, can selectively modulate the behavior of Piezo channels. Moreover, redistributing charged components within the membrane can modify its mechanical properties. This induced membrane tension can open Piezo channels, leading to an influx of calcium. This ion flux is crucial, as it activates intracellular signaling pathways and influences cellular activities, such as proliferation, migration, and gene expression¹⁰⁴, as shown in Fig. 4c. The responsiveness of Piezo channels to electric fields enhances our understanding of how electrical stimulation can be leveraged to control cellular functions, offering promising strategies for therapeutic interventions in various diseases.

Optical stimulation of Piezo channels

Moreover, we emphasize the significance of optical modulation techniques for Piezo channels. Using light-sensitive beads, proteins, or molecules, Piezo channel activity can be precisely modulated by optical stimulation. Optical stimulation provides exceptional spatial and temporal precision, making it a robust tool for investigating mechanotransduction mechanisms in physiological and pathological contexts.

Optical control (light-gated Piezo1)

Optical tweezers utilize a focused laser beam to exert attractive or repulsive forces on beads attached to Piezo channels, forming an optical trap that activates Piezo channels, thereby inducing calcium influx^105,106, as shown in Fig. 5a. Falleroni et al. used oscillatory optical tweezers to apply forces ranging from 5 to 50 pN on neurons and observed the corresponding Piezo channel responses¹⁰⁷. A single indentation can trigger a transient increase in intracellular calcium, while repeated indentations lead to more sustained and varied calcium responses. Neurons can discern the magnitude of mechanical forces and respond through Piezo channels, which activate the CaMKII and RhoA signaling pathways under physiological conditions¹⁰⁶.

Fig. 5. Optical stimulation of Piezo channels.

a Optical tweezers use a focused laser beam to create an optical trap, applying mechanical forces on particles attached to Piezo channels, which then causes calcium influx. b Optogenetics uses targeted laser light to activate specific genes, leading to precise optical responses that trigger Piezo channel activity. c Chemical optogenetics involves modifying Piezo channels with chemically engineered ligands, allowing them to respond to specific laser wavelengths

Optogenetics stimulation

Optogenetics combines optics and genetics to modulate the gain or loss of function in targeted cells within living tissues^108,109. It uses lasers to activate genetically encoded light-sensitive proteins, enabling optical control over Piezo channels-related cellular activity¹¹⁰, as shown in Fig. 5b. Zeng et al. engineered Piezo2Cre⁺; ChR2-eYFP mice crossing Piezo2^GFP-IRES-Cre (Piezo2Cre) knock-in mice with Cre-dependent channelrhodopsin-2 (ChR2) reporter mice. Cardiovascular responses were recorded following activating Piezo2-positive vagal sensory nerve regions using optogenetics¹¹¹. Optical fibers were positioned on the vagus nerve trunk, the superior laryngeal branch, and the carotid sinus. The carotid sinus and vagus nerves were illuminated to activate ChR2-expressing Piezo2-sensory neurons. These findings suggest that Piezo channels can be effectively regulated using optogenetic methods.

Optochemical modulation

Chemical optogenetics combines gene-targeted chemical modulation with optical regulation of signaling pathways^112,113. This approach uses light-activated chemical ligands to regulate Piezo channels via specific, light-sensitive chemical ligands. Chemical methods modify Piezo channels to render them responsive to specific laser stimuli, as shown in Fig. 5c. Peralta et al. engineered light-responsive Piezo channels in mice by conjugating an azobenzene-based photoswitch to a particular site on the channel¹¹⁴. This modification mimics the natural mechanical activation of Piezo channels, enabling the channel to open in response to light. The light-induced conformational change in azobenzene exerts a localized force, activating the channels more gradually compared to direct mechanical pressure.

Magnetic stimulation of Piezo channels

Magnetic stimulation offers significant advantages, as it can be used across a wide range and penetrates deeply into tissue noninvasively with minimal attenuation, making it highly effective for in vivo applications¹¹⁵. The magnetic field can be strategically coupled to the particle to target, manipulate, and activate Piezo channels on specific cells. Adjusting the strength of the magnetic field¹⁰⁹ can readily modulate stress parameters. Here, we summarize the various methods of magnetic stimulation applied to Piezo channels.

Magnetic twisting

Magnetic particles can rotate and generate torque when exposed to an external magnetic field. This torque can subsequently be transmitted to the membrane through a twisting field, inducing the membrane stretching and activating Piezo channels, thereby facilitating calcium influx¹¹⁶. Magnetic nanoparticles have been utilized to generate magnetic forces, mediating calcium influx in neuronal cells subjected to a high magnetic gradient¹¹⁷, as shown in Fig. 6a. Gregurec et al. reported that magneto-mechanical stimulation using anisotropic magnetite nanodiscs could apply torques to cell membranes¹¹⁸. Magnetite nanodiscs generate nondisruptive torque to activate Piezo channels between vortex and in-plane magnetizations under weak and slow magnetic fields. This approach enables pulsed modulation of calcium influx in sensory neurons and activation of Piezo channels through magnetic field intensities. The torque generated by large magnetic discs (MDs) triggers responses in multiple mechanosensitive ion channels, while smaller MDs specifically activate Piezo channels through shear stress¹¹⁹. Magnetic twisting plays a critical role in the development of magneto-mechanical therapies and offers valuable insights into the behavior of primary cortical neurons¹²⁰.

Fig. 6. Magnetic stimulation of Piezo channels.

a Magnetic twisting: particles are capable of rotating and generating torque when subjected to an external magnetic field. This torque can be transmitted to the membrane via a twisting field, thereby activating Piezo channels and facilitating calcium influx. b Targeted channel: magnetic nanoparticles are conjugated to Piezo channels through the use of antibodies. Piezo channels are prompted to open under a high-gradient magnetic field. c Clustering: magnetic particles are dispersed along the membrane surface in the absence of a magnetic field. When a high-gradient field is applied through a magnetic needle, the particles are attracted toward the source of the field, leading to clustering that deforms the membrane and activates Piezo channels

Targeted channel

Magnetic nanoparticles are conjugated to Piezo channels through specific antibodies. Piezo channels open upon activation by a high-gradient magnetic field¹²¹, as shown in Fig. 6b. Lee et al. modified Piezo channels with a Myc tag and developed an anti-Myc m-Torquer to specifically target Piezo channels and generate the torque forces¹²². Upon exposure to a rotating magnetic field, the m-Torquer-treated neurons experience a force of approximately 1.6 pN on the Piezo channels, producing calcium signal fluorescence. This strategy offers the distinct advantage of selectively activating a single ion channel without affecting other channels on the membrane. Targeted activation of Piezo channels is more efficient. It requires less force than other methods, such as membrane deformation or cytoskeletal disruption¹¹⁷. This exact targeting method allows for independent cellular control.

Magnetic clustering

Magnetic particles are dispersed across the membrane surface without a magnetic field. Upon application of a high-gradient magnetic field, the particles migrate toward the field source. This movement causes the particles to cluster, leading to the membrane deformation and subsequent activation of Piezo channels¹²³, as shown in Fig. 6c. Lee et al. conjugated magnetic nanoparticles to the surface of individual auditory hair cells¹²⁴. An electromagnetic microneedle actuator concentrated a high-gradient magnetic field on the submicrometre-sized areas, with the field vector oriented at a small angle to the cell layer plane. The magnetic field within the needle induces clustering of the receptors as the particles migrate toward the field source, activating Piezo channels and associated signaling pathways. Clustering can be induced in specific cells as the nanoparticles are attracted toward the field. This process demonstrates potential as a biosensor, leading to intracellular calcium influx mediated by clustered Piezo channels^125,126.

Comparison of different stimulation methods

Mechanical stimulation, electrical stimulation, optical stimulation, and magnetic stimulation all offer distinct advantages for activating Piezo channels, each with its own set of strengths and limitations, as shown in Table 2.

Table 2.

A comparison table of different stimulation methods

Methods	Contents	Quality/Long-term safety	Off-target effects	Side effects/Mechanical stimulation risk	Ref.
Mechanobiological stimulation	Vibration less than 20 kHz	• Mechanical stimulation is effective in in vitro and animal models. • Long-term use may cause cell damage or tissue dysfunction, especially with high-intensity stimulation.	• Activate other mechanosensitive channels and affect neighboring tissues. • May trigger non-specific target.	• Side effects include membrane damage, muscle spasms, and tissue injury. • Cavitation effects may lead to cell rupture and apoptosis with excessive stimulation.	75,76
	Vibration more than 20 kHz
Electrical stimulation	Membrane potential	• Piezo channel can be activated through potential changes. • Long-term overactivation may lead to calcium overload or channel inactivation.	• Potential changes may affect other voltage-sensitive channels.	• Excessive voltage could lead to membrane damage or cell dysfunction.	102,127,128
	Electric field
	Particle-mediated	• Nanoparticles effectively activate Piezo channels in in vitro models. • Long-term safety of nanoparticle accumulation and toxicity in vivo needs more research. • Reproducibility is challenged by heterogeneous cellular uptake.	• Nanoparticles may have non-specific interactions with other receptors or channels in the membrane.	• Nanoparticle toxicity may affect cell viability or cause an immune response.
Optical stimulation	Optical tweezers	• Provides high spatial and temporal precision for activating Piezo channels. • Limited long-term safety and reproducibility data, especially for optogenetic and chemical optogenetic approaches.	• Potentially influence non-specific activation of other light-sensitive proteins or channels.	• Potential inflammation and immunogenicity caused by optogenetic tools. • Chemical optogenetic agents also require rigorous validation.	129,130
	Optogenetics
	Chemical optogenetics
Magnetic stimulation	Magnetic twisting	• Magnetic stimulation is non-invasive with minimal attenuation in deep tissue. • Long-term safety data of repeated exposure to high-gradient magnetic fields are limited.	• Magnetic discs or nanoparticles may cause non-specific ion channel activation.	• Excessive force from magnetic twisting may cause calcium overload or neuronal toxicity.	131,132
	Targeted channel
	Clustering

Mechanobiological modulation

Mechanical stimulation is effective in in vitro and animal models, but long-term use may cause cell damage or tissue dysfunction, especially with high-intensity stimulation⁷⁶. Furthermore, it lacks target specificity and may inadvertently activate other mechanosensitive channels, adversely affecting adjacent tissues. Severe side effects, particularly from cavitation, can include membrane disruption, muscle spasms, cell rupture, and apoptosis⁷⁵.

Electrical stimulation

Direct electrical stimulation risks the long-term overactivation of Piezo channels, potentially disrupting ionic homeostasis and inducing cellular dysfunction¹²⁷. The risk of non-specific activation of other voltage-sensitive channels remains a concern¹²⁸. In addition, the in vivo long-term safety and toxicity of particle-mediated stimulation remain unclear and requires further investigation¹⁰².

Optical stimulation

Although optical stimulation offers high spatiotemporal precision, there is limited long-term safety data regarding repeated exposure, especially for optogenetic and chemical optogenetic methods¹²⁹. Key translational hurdles include potential immunogenicity and inflammation, as well as the off-target activation of other light-sensitive proteins. Furthermore, the toxicity and side effects of chemical optogenetic agents demand rigorous in vivo validation¹³⁰.

Magnetic stimulation

While advantageous for deep-tissue penetration, long-term safety data of repeated exposure to high-gradient magnetic fields are limited¹³¹. The use of magnetic discs or nanoparticles risks non-specific ion channel activation. Moreover, excessive mechanical force generated by magnetic twisting may induce severe calcium overload and subsequent cellular or neuronal toxicity¹³².

Overall, while these modalities are powerful research tools, rigorous in vivo safety evaluations, particularly concerning long-term effects, off-target effects, and chronic stimulation risks, must be completed before any clinical translation can be realized.

Stimulation of Piezo channels of brain cells

Finally, we explore the potential applications of Piezo channel modulation in neurodegenerative diseases, a promising avenue with the potential to profoundly impact healthcare. Piezo1 channels are mainly expressed in non-neuronal cells, such as various subtypes of glial cells, to sense twisting, turning, ratcheting, flexing, compressing, expanding, and bending. It is key in mediating neuronal signaling and promoting central nervous system plasticity²¹. Piezo2 channels are mainly expressed in primary sensory neurons to sense gentle touch^133,134, tactile pain^135,136, proprioception^137,138, airway stretch and lung inflation¹³⁹, baroreceptive reflex¹¹¹, and low-threshold bladder-stretch and urethral micturition¹⁴⁰.

Neuron

In neurons, Piezo2 channels are primarily expressed in sensory neurons, where they are crucial for mediating proprioception, touch perception, and mechanosensation¹³⁹. Piezo2 channels participate in a range of physiological and pathological processes in neurons. In proprioceptive sensory neurons, Piezo2 deficiency suppresses allodynia development and reduces mechanical stimulus sensitivity in neuropathic pain¹⁴¹, as shown in Fig. 7a. Additionally, in vagal sensory neurons, Piezo2 deletion leads to respiratory distress and diminished responsiveness to lung inflation. Piezo2 channels are airway stretch sensors, essential for normal breathing¹³⁹, as shown in Fig. 7b. Furthermore, in innervating sensory neurons, Piezo2 channels act as mechanosensors in the urinary system¹⁴⁰, as shown in Fig. 7c. Piezo2 expression in lower urinary tract tissues is essential for low-threshold bladder-stretch sensing and the urethral micturition reflex. Humans deficient in Piezo2 channels experience impaired bladder control and lack bladder-filling sensation. These findings underscore the role of Piezo2 channels and provide a foundation for the development of targeted therapies for sensory dysfunctions and pain management.

Fig. 7. Activation of Piezo channels in brain cells.

Piezo1 is predominantly found in non-neuronal cells, while Piezo2 is primarily expressed in sensory neurons. a In proprioceptive sensory neurons, the absence of Piezo2 inhibits the onset of allodynia. b In vagal sensory neurons, removing Piezo2 results in respiratory distress and reduced responsiveness. c In sensory neurons that innervate the urinary system, Piezo2 channels function as mechanobiological sensors. d Piezo1 channels are involved in regulating the NF-κB/mTOR signaling pathways. e Piezo1 channels allow astrocytes to change their shape and activity in response to substrate stiffness and mechanical forces through calcium signaling. f Piezo1 channels are essential for controlling oligodendrocyte maturation

Microglia

Microglia are essential for immune defense in the central nervous system and exhibit mechanosensitive behaviors modulated by Piezo1 channels^142,143, as shown in Fig. 7d. Mechanical signaling is a validated trigger for microglial inflammatory activation¹⁴². Piezo1 fundamentally regulates microglial migration patterns in response to substrate stiffness. Furthermore, it is well documented that Piezo1 modulates the pro-inflammatory response during microglial activation by lipopolysaccharide^143–145, a commonly used surrogate for bacterial infection that elicits transient changes in microglial gene expression¹⁴⁶. Beyond these established roles, the hypothesis that Piezo1 regulates microglial morphological remodeling and inflammation under specific metabolic stress, such as high-glucose conditions via the JNK and mTOR pathways, remains speculative^147,148. While promising, this pathway implication is largely derived from indirect data and requires rigorous in vivo experimental confirmation.

Astrocytes

Astrocytes play a central role in maintaining homeostasis in the central nervous system, with diverse functions, including ion regulation, neurotransmitter clearance, synapse formation and removal, and neurovascular coupling^149–151. Astrocytes form tripartite synapses and the blood-brain barrier (BBB), which is significant for synaptic output regulation and detection¹⁵². Piezo1 channels allow astrocytes to adjust their morphology and activity in response to substrate stiffness and mechanical forces via calcium signaling, thereby affecting interactions with neurons and neural stem cells³⁸, as shown in Fig. 7e. Piezo1 channels also regulate ATP release, essential for neural stem cell proliferation^153,154. Additionally, Piezo1 channels are associated with neuroinflammation and cytokine release. The dual localization of Piezo1 channels at the membrane and in the endoplasmic reticulum enhances intracellular calcium dynamics and modulates inflammatory responses^155,156. Regulation of Piezo1 channels in astrocytes highlights their critical role in both the physiology and pathology of the central nervous system.

Oligodendrocyte

Myelin formation and repair are essential for nerve impulse transmission, with oligodendrocytes (OLs), glial cells responsible for myelination, originating from oligodendrocyte progenitor cells (OPCs)¹⁵⁷. Piezo1 channels have emerged as a significant regulator of oligodendrocytes, modulating their response to mechanical force in the brain microenvironment^158,159, as shown in Fig. 7f. It is firmly established that Piezo1 acts as a critical mechanosensor in OPCs. In vivo evidence demonstrates that age-related tissue stiffening activates Piezo1 to restrict OPC function, and that the genetic knockdown or inhibition of Piezo1 in aged central nervous system lesions significantly enhances OPC regeneration¹⁵⁹. Conversely, while in vitro pharmacological studies show that Piezo1 inhibitor GsMTx4 promotes, whereas the activator Yoda1 suppresses the proliferation and migration of oligodendrocytes, the precise downstream mechanisms remain highly speculative¹⁶⁰. The exact impact of Piezo1 activation on dynamic in vivo myelination and remyelination processes requires substantial further functional validation.

Regulating various physiological processes by activating Piezo channels

This section clarifies recent developments in the activation of Piezo channels. These channels are crucial for regulating various physiological processes, such as those in the nervous and immune systems, heart failure, cancer, bone remodeling, and lung injury. We outline the main signaling pathways triggered by Piezo channels.

Nervous system

Piezo channels significantly impact the nervous system, influencing various cell types, including neural progenitors, neurons, myelinating oligodendrocytes, immune-active microglia, supportive astrocytes, and vascular endothelial cells¹⁶¹. These cells exhibit significant mechanosensitivity, where mechanical forces modulate Piezo channels in their membranes, affecting cellular behaviors and physiological responses¹⁶². Piezo channels are crucial for neural growth, neuroinflammation, angiogenesis, and the regulation of cerebral blood flow^154,163,164. Piezo channels have dual effects in neurons: they regulate neuronal plasticity through the CaMKII/CREB signaling pathway while inhibiting axonal regeneration via the CaMKII/NOS pathway, as illustrated in Fig. 8a.

Fig. 8. Recent advancements in activating Piezo channels and their regulatory effects on various physiological processes, including the nervous system, immune system, heart failure, cancer, bone remodeling, and lung injury.

a Piezo channels exhibit dual effects in neurons: regulating neuronal plasticity via the CaMKII/CREB signaling pathway and inhibiting axonal regeneration via the CaMKII/NOS pathway. b Hydrostatic pressure-induced activation of Piezo channels triggers calcium influx and activates the AP1/HIF-1α pathway. c Mechanical overload increases Piezo expression in cardiomyocytes via the CaMKII-HDAC4-MEF2 pathway, ultimately leading to dilated cardiomyopathy. d The MAPK pathway modulates YAP signaling to inhibit the growth and development of liver cancer. e Piezo channel activation triggers calcium influx, stimulating calcineurin and promoting the coordinated activation of NFATc1, YAP1, and β-catenin transcription factors in response to mechanical forces. f Elevated Piezo expression is observed in cyclic stretch-treated pulmonary cells under high tidal volume ventilation

Immune system

Piezo channels are essential for the function of various immune cells, including macrophages, dendritic cells, and T lymphocytes¹⁶⁵. Upon stimulation, innate immune cells amplify danger signals by releasing chemokines, cytokines, and other inflammatory mediators, including tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and IL-6, which are associated with many diseases¹⁶⁶. This inflammatory response promotes the recruitment and activation of adaptive immune system cells, such as T and B lymphocytes. Dysregulation of immune reactions can lead to chronic inflammation, potentially resulting in extensive tissue damage. Mechanical stimulation of Piezo channels in immune cells can lead to excessive, uncontrollable inflammation, potentially causing systemic damage, including cardiovascular disease and knee osteoarthritis¹⁶⁶. Mechanical stretching affects macrophage polarization and amplifies inflammatory signaling pathways in cellular models^144,167. Macrophages are classified into M1 macrophages, which exhibit pro-inflammatory properties, and M2 macrophages, which are associated with anti-inflammatory responses¹⁶⁸. Activation of Piezo channels by hydrostatic pressure induces calcium influx and activates the AP1/HIF-1α signaling pathway¹⁶⁹, as shown in Fig. 8b. This mechanism promotes macrophage differentiation into M1-like macrophages, which secrete pro-inflammatory cytokines¹⁴⁴.

Heart failure

Heart failure can be triggered by inflammation and fibrosis. In cardiac tissues, detrimental mechanical forces not only cause direct physical damage but also induce indirect damage by releasing pro-inflammatory factors¹⁷⁰. Piezo channels act as key mechanosensors in the heart, crucial in regulating and repairing cardiac injury¹⁷¹. Endothelial cells, cardiac fibroblasts (CFs), and cardiomyocytes (CMs) are subjected to varying degrees of physical stimulation, which activates Piezo channels^172,173. Mechanical stress triggers Piezo channel activation in fibroblasts, promoting IL-6 expression through the p38α MAPK signaling pathway¹⁷⁴. Mechanical overload increases Piezo expression in cardiomyocytes through the CaMKII-HDAC4-MEF2 pathway, ultimately leading to dilated cardiomyopathy, as illustrated in Fig. 8c.

Cancer

Piezo channels play a critical role in modulating the development of various tumors¹⁶⁵, such as stomach cancer¹⁷⁵, colon tumors¹⁷⁶, hepatocellular carcinoma¹⁷⁷, lung cancer¹⁷⁸, breast carcinoma¹⁷⁹, oral squamous cell carcinoma¹⁸⁰, and pancreatic ductal adenocarcinoma¹⁸¹. Piezo channels have been demonstrated to play a critical physiological role¹⁷⁷ in hepatocellular carcinoma. Piezo channels are highly expressed in HepG2 cell lines. The lack of Piezo channels correlates with the proliferation, migration, and apoptosis of liver cancer cells. The activation of Piezo channels induces calcium influx into hepatocellular carcinoma cells. It triggers the phosphorylation of c-Jun N-terminal kinases (JNK), p38 mitogen-activated protein kinase (p38 MAPKs), extracellular signal-regulated protein kinases (ERKs), and the mitogen-activated protein kinase (MAPK) pathway. The MAPK signaling pathway regulates YAP signaling to inhibit liver cancer growth and development, as illustrated in Fig. 8d.

Bone remodeling

Piezo channels are important mechanosensors in the skeletal system and regulate skeletal homeostasis^182,183. Physiological mechanical stimulation is essential for normal bone and joint function¹⁸⁴. In osteoblasts, Piezo channel activation triggers calcium influx, stimulating calcineurin and promoting the coordinated activation of NFATc1, YAP1, and β-catenin transcription factors in response to mechanical forces¹⁸⁵, as shown in Fig. 8e. However, excessive mechanical stress can lead to inflammation and degeneration. In osteoarthritis (OA), high mechanical strain upregulates Piezo expression in chondrocytes, enhancing calcium signaling and inducing cell apoptosis^186,187. Furthermore, the MAPK/ERK5 and MAPK/ERK1/2 pathways activated by Piezo channels influence late-stage chondrocyte apoptosis under elevated strain conditions^188,189.

Lung injury

Mechanical ventilation can cause lung injury, commonly called ventilator-induced lung injury (VILI)^190,191. Piezo channels play a critical role in mechanotransduction, converting mechanical stimulation into calcium influx and thereby regulating cytoskeletal reorganization and stress responses¹⁹², as shown in Fig. 8f. Under high tidal volume ventilation, Piezo expression increases in cyclic stretch-treated pulmonary cells, activating the RhoA/ROCK1 signaling pathway¹⁹³. Inhibition of the RhoA/ROCK1 signaling pathway has been shown to significantly mitigate high ventilation and lipopolysaccharide-induced lung injury^194,195.

Conclusions

Over the past decade, our knowledge of the complex processes involving Piezo channel mechanotransduction has expanded rapidly. However, many questions still persist. For instance, we still lack a clear understanding of the exact physical gating mechanism of mechanosensory channels. Most research centers on how ultrasound affects Piezo1 channels, but often does not include detailed models of ultrasound activation. Moreover, observing real-time mechanotransduction remains challenging. While cryo-EM can reveal static structures of Piezo channels, it’s unclear whether high-speed microfluidic imaging can capture their dynamic functions. Improving the spatial and temporal resolution of mechanical simulations is crucial, especially for studying Piezo channels in individual cells. Most current studies focus on proteins from large cell groups, but single-cell approaches using acoustic or magnetic tweezers could provide valuable insights. Finally, developing safe, non-invasive devices to stimulate Piezo channels for neural regeneration in clinical practice is an exciting prospect. While promising, translating these advancements into medical applications will require careful adaptation and safety considerations. Addressing these challenges is essential for advancing new Piezo-based therapies and enhancing healthcare globally.

Moreover, epigenetic mechanisms, including DNA and histone modifications, are increasingly recognized as key regulators of neurogenesis¹⁹⁶. Mechanical cues, such as matrix stiffness, viscoelasticity, and fluid shear stress, have been shown to reshape chromatin organization and modulate epigenetic states, thereby promoting cell reprogramming^197–199. As a form of mechanical stimulation, ultrasound can exert epigenetic effects through mechanisms related to sonoepigenetics⁸. Further investigation into the crosstalk between ultrasound and epigenetic regulation may deepen our understanding of the mechanisms governing cell reprogramming and neurogenesis, and may offer new opportunities for the development of innovative therapeutic strategies.

While the proposed mechanistic models of Piezo channels offer a complementary, multi-scale framework for understanding mechanotransduction, it is essential to distinguish well-supported structural facts from in silico proposals and functional extrapolations. The foundational architecture of modularization mechanisms is validated by high-resolution cryo-EM and X-ray crystallography. However, the dynamic physical movements of these components during real-time gating remain experimentally unverified. Furthermore, the membrane dome and curvature sensing mechanisms rely heavily on free-energy calculations, currently lacking validation within complex and native lipid environments. Similarly, the lever-like, plug-and-latch, and dual-gating models are hypotheses largely extrapolated from static structures or in vitro electrophysiology. These mechanistic conclusions, which are based on in silico or otherwise uncertain proposals, require further experimental validation. Moreover, a major challenge is to further verify these proposed mechanisms using reproducible approaches that bridge structural, computational, and functional data under more physiological conditions.

Mechanical, electrical, optical, and magnetic stimulation modalities, while powerful experimental tools, still face major safety and validation gaps. First, while potential sensitivity acts as a tuner for mechanical thresholds in Piezo channels, its role across diverse tissues lacks experimental validation and carries risks of non-specific activation of other potential-sensitive channels. Second, the generalizability of in vitro results to in vivo systems is limited by the absence of the complex 3D extracellular matrix and systemic cytoskeletal coupling found in living organisms. This is particularly evident in particle-mediated stimulation, where the long-term biocompatibility, tissue toxicity, and heterogeneous cellular uptake of nanoparticles remain largely uncharacterized. Third, significant safety concerns persist across all stimulation modalities: excessive mechanical or magnetic force can lead to calcium overload and apoptosis, while prolonged electrical or optical stimulation can disrupt ionic homeostasis and trigger immune responses. Consequently, these modalities should currently be viewed as powerful research tools rather than clinically ready interventions. Rigorous, long-term in vivo evaluations of off-target effects and chronic toxicity are mandatory before any translational aims can be realized.

Although various pathways yield promising readouts, Piezo-based biomarkers have yet to achieve the validation necessary for clinical translation, as most disease correlations still lack rigorous in vivo confirmation. Based on current evidence, glial Piezo1, specifically within microglia and the oligodendrocyte lineage, represents the most plausible therapeutic target for neurodegeneration. Unlike more descriptive models, these pathways are directly supported by functional data linking them to inflammatory activation, mechanosensing of age-related tissue stiffening, and regeneration failure in chronic lesions. By contrast, astrocytic Piezo1 remains mechanistically important but less clearly linked to actionable disease pathways, and Piezo2 is better supported in sensory dysfunction than in core neurodegenerative progression.

In summary, it is a critical time to recognize the importance of Piezo channels and their future applications in sonogenetics and sonoepigenetics. In particular, Piezo 1 channels, distinguished mechanosensitive ion channels, are located not only on cell membranes but also on the nuclear envelope, where they convert mechanical stimuli into epigenetic signals and modulate gene expression. These intriguing pathways identify mechanical stress, nuclear deformation, and substrate stiffness, thereby facilitating calcium ion influx into the nucleus. This process alleviates nuclear rigidity and enhances access to chromatin, thereby supporting healthy cellular function. This offers promising prospects for advancing noninvasive techniques such as sonogenetics and sonoepigenetics.

Author contributions

L.P.L., Y.P. and H.C. shaped ideas and provided guidance. Y.P. researched data for the article. Y.P. prepared the figures and wrote the manuscript with assistance from L.P.L. All authors contributed to discussing the contents and reviewed and edited the manuscript.

Conflict of interest

The authors declare no competing interests.