Piezo mechanosensitive channels: A biological hub for intestinal barrier homeostasis and an emerging target for disease intervention

Abstract

Intestinal homeostasis is regulated by a variety of signals such as mechanical signals, immunity and metabolism, and they need to be coordinated. However, how mechanical signals affect the intestinal barrier at the molecular level has not been fully figured out. The Piezo channels is an important sensor in cell mechanical transduction, which is common in mechanically sensitive cells in the intestine. Studies show that these channels are involved in intestinal development, and are also used to regulate barrier function and play a role in the immune regulation process. In existing studies, the Piezo channels help to repair the intestinal epithelium, promote mucus secretion, modulate immune responses, and mediate 5-hydroxytryptamine secretion by enterochromaffin cells. Therefore, it can be seen that the Piezo channel can maintain the integrity of the barrier, regulate intestinal peristalsis and visceral sensation. Once the function of the Piezo channel is abnormal, the intestinal barrier will be damaged and the inflammation will be aggravated. This change further promotes the occurrence of chronic diseases such as inflammatory bowel disease, irritable bowel syndrome and colon cancer. Relevant studies have found that researchers can regulate the Piezo channel through the agonist Yoda1 or the inhibitor grammostola spatulata mechanosensitive channel toxin 4, which has been used to alleviate symptoms and also provides new the idea of treatment. This article discusses the role of Piezo channel in maintaining intestinal homeostasis, and focuses on its impact on barrier integrity, immune regulation and intestinal peristalsis. At the same time, the article also analyzes the relationship between Piezo channels abnormal function and inflammatory bowel disease, irritable bowel syndrome and cancer, and discusses the clinical treatment methods targeting these channels.

Key Words: Intestinal barrier; Intestinal diseases; Mechanosensation; Piezo channel; Targeted therapy

Core Tip: Piezo mechanical sensitive channel is the core mechanical transduction hub for maintaining intestinal homeostasis, which can convert mechanical force into biological signals. They regulate a complex network encompassing epithelial renewal, barrier integrity, immune response and gastrointestinal dynamics. Piezo channel dysfunction can directly drive the development of inflammatory bowel disease, irritable bowel syndrome and colon cancer. Therefore, the pharmacological regulation of the Piezo channels by using specific drugs such as the agonist Yoda1 or the inhibitor grammostola spatulata mechanosensitive channel toxin 4 can provide a promising treatment strategy for the intestinal diseases.

INTRODUCTION

The intestine is a key part of the digestive system, responsible for nutrient intake, digestion, and absorption[1]. In fact, as the body’s largest immune organ[2], the gut has established a dynamic and complex defence network through the synergistic interaction between the epithelial barrier, the mucosal immune system and the symbiotic microbiota. When intestinal function is impaired, its fundamental absorptive capacity is directly compromised[3], and long-term dysfunction may result in weight loss and malnutrition. Malabsorption is mostly related to the imbalance of intestinal microbiota[4]. When the state of these microbial changes, the barrier integrity and immunomodulation function will be damaged. At the same time, pathogenic bacteria are more likely to multiply and increase the level of systemic inflammation. The intestine plays an important role in the body’s immune defense, so once its function is impaired, the risk of local and distal organ infection will also increase[5]. Therefore, understanding the systemic nature of gut homeostasis is essential for advancing both basic biological research and clinical therapeutic strategies.

The establishment of intestinal functional homeostasis depends not only on immune regulatory networks but also on its intrinsic mechanical activity and precise sensing of mechanical stimuli. Mechanosensation is the core mechanism governing intestinal motility. It transduces mechanical forces into physiological signals to sustain intestinal normal function[6]. Under physiological conditions, the intestinal tract is consistently exposed to multiple mechanical stresses, including peristaltic contractions, villous motility, intraluminal pressure, and mucosal distortion[7]. Mechanosensitive ion channels act as key molecular sensors of these mechanical forces. In the intestine, channels including the transient receptor potential (TRP) family, two pore potassium channels, voltage-gated sodium and calcium channels, and large-conductance calcium-activated potassium channels channels have been shown to participate in intestinal mechanotransduction, among which Piezo channels are particularly critical[8]. In 2010, Coste et al[9] identified a mechanosensitive ion channel protein, Piezo1, via a functional screen of the Neuro2A neuroblastoma cell line. Subsequently, its homologous subtype Piezo2 was further identified based on sequence homology[10]. Piezo channels exhibit a unique homotrimeric three-bladed propeller-like structure composed of a central ionic conductive pore, an extracellular cap, and three curved non-planar blades that extend intracellular beams. This “bowl-shaped” structure generates local membrane curvature, forming a dome-like structure. Deformation of the surrounding lipid bilayer increases membrane tension, which enhances the sensitivity to external mechanical stimuli[11]. When membrane tension changes, the blades and beams undergo significant conformational changes, driving the gating of the ionic conductive pore. Piezo channels convert mechanical forces into ion flow through structural rearrangement, thus playing a role in a variety of physiological processes. Piezo1 is a large cation channel with high calcium (Ca²⁺) permeability. The channel can respond to a variety of mechanical stimuli, such as hydrostatic pressure, fluid shear stress and stretching[12]. Studies have found that Piezo1 is expressed in the gastrointestinal wall[13], digestive glands[14] and the enteric nervous system[15]. In contrast, Piezo2 is highly and specifically expressed in sensory neurons and enterochromaffin (EC) cells[16], playing a key role in visceral sensation and the regulation of intestinal motility. Recent studies have confirmed that Piezo channels are stably expressed in diverse intestinal cell types[17], where they contribute to maintaining epithelial barrier integrity, regulating gut motility, and mediating therapeutic responses[8].

On this basis, this paper systematically reviews the multi-level mechanisms of Piezo channel in maintaining intestinal homeostasis, and analyzes its pathogenic role in inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and colon cancer. It also evaluates potential intervention strategies targeting Piezo channels, aiming to provide a novel theoretical framework for mechanistic research and precision therapy of intestinal diseases from a biological perspective.

PIEZO CHANNELS: A “DOUBLE-EDGED SWORD” IN INTESTINAL BARRIER HOMEOSTASIS

Piezo channels promote intestinal development and epithelial renewal

As the primary site of nutrient absorption and metabolic transformation, the intestine undergoes structural development and functional maturation that are fundamental for maintaining homeostasis. Intestinal development is a highly spatiotemporally regulated process that depends on the coordinated control of multiple signaling networks. Classical pathways, such as adenosine 5’-monophosphate-activated protein kinase (AMPK)[18] and Wnt[19], participate in intestinal tissue and cellular development, with mechanosensory mechanisms playing a crucial role. As a mechanically sensitive ion channel, the Piezo channel is widely distributed in the intestine, which provides a molecular basis for the conversion of mechanical signals into cell transcription and metabolic reactions.

The orderly turnover of intestinal epithelial cells (IECs) is essential for maintaining the integrity and function of the intestinal barrier. The human intestinal epithelium is renewed about every 3 to 5 days, which is driven by the proliferation of intestinal stem cells (ISCs) at the bottom of the crypt[20]. As an important part of mechanical sensation, Piezo protein can respond to stimuli such as lumen expansion and peristalsis stretching, and mediate the inflow of cross-membrane calcium ions[21]. Subsequently, this calcium signal regulates cryptore division and cell proliferation, thus producing new IECs[22]. Mechanical signals not only come from the external environment, but also participate in regulating the rhythm of stem cell fate and tissue renewal. Research on different species also supports this phenomenon. In fruit flies, IECs do not have a typical “crypt-villi” structure, but mechanical stimulation can still change the epithelial structure and affect cell differentiation[23]. Physiological distension of the Drosophila midgut activates Piezo channels in enteroendocrine cells, triggering a Ca²⁺ influx that drives enteroendocrine cell progenitor differentiation and proliferation[24,25]. These research results show that the Piezo channel enables IECs and their precursor cells to perceive mechanical forces and convert them into intracellular signals, thus regulating the process of cell proliferation and differentiation in different species. The mechanical transduction process supports the continuous renewal of epithelial tissue while maintaining the integrity of its structure. Mechanical signals provide a new understanding for the formation and maintenance of the intestinal barrier by connecting the physical stimulation and epithelial regeneration process in the lumen environment.

Dual regulatory role of the piezo channel in the intestinal barrier

The intestinal barrier consists of a mucus layer, a physical barrier formed by tight junctions between epithelial cells, and an immune defense barrier[26]. Multiple components interact to form a multi-layer defense network in dynamic regulation. The Piezo channel not only participates in the protection process, but also plays a dual role. In the normal physiological state, moderate mechanical stimulation can promote the proliferation and differentiation of ISCs by activating the Piezo channel, which helps to maintain the homeostatic state of the intestinal barrier. When pathological conditions such as IBD, IBS or colon cancer occur, continuous excessive stretching or abnormal mechanical force will act on the channel, which may cause excessive activation or dysfunction, which then affect the regenerative ability of epithelial cells or lead to damage to the intestinal barrier.

Piezo channels induce mucin2 secretion to maintain intestinal mucus barrier homeostasis: The intestinal mucus barrier is located between the host and the intestinal microbiota and acts as the first defensive structure. The barrier is composed of a mucus layer covering the surface of the epithelium, digestive juice and antibacterial peptides. A variety of components cooperate with each other to form a barrier structure with both physical and biochemical functions, thus protecting the lower epithelial tissue. The mucus layer is mainly composed of mucoprotein, water, lipids and other substances. In this system, IECs can be differentiated into many types, including intestinal cells, intestinal endocrine cells, goblet cells, Pan cells and M cells[27]. Mucin is one of the components of the intestinal mucus layer, primarily secreted by goblet cells[28], and plays a role in maintaining intestinal homeostasis. Studies have shown that Piezo1 is highly expressed in goblet cells. Upon receiving physiological mechanical stimuli, Piezo1 promotes the secretion of Mucin2 through the extracellular signal-regulated kinases/Ca²⁺ pathway[29]. Further mechanistic studies indicate that Piezo1 is involved not only in regulating secretion but also in Mucin2 transcription and synthesis through epigenetic mechanisms. When Piezo1 channels in goblet cells are activated, the suppressor of variegation 3-9 homolog 1-histone H3 lysine 9 trimethylation pathway is inhibited, which relieves the suppression of Mucin2 gene transcription and enhances Mucin2 secretion[30]. Mucin2, as the most abundant mucin secreted in the gastrointestinal tract, is a major component of the intestinal mucus layer[31] (Figure 1A). Therefore, when Piezo1 expression or function is impaired, Mucin2 synthesis and secretion are reduced, thinning the intestinal mucus layer and making the intestinal microbiota more accessible to the epithelial surface, leading to gut dysbiosis and increased risk of chronic inflammation.

Figure 1 Piezo regulates intestinal mucosal and epithelial barrier through multiple signaling pathways. A: In the mucosal barrier, Piezo1 promotes Mucin2 secretion via the extracellular signal-regulated kinase/Ca²⁺ pathway and inhibits the suppressor of variegation 3-9 homolog 1-histone H3 lysine 9 trimethylation pathway; B: In the epithelial barrier, Piezo1 suppresses Claudin-1 expression through Rho-associated coiled-coil containing protein kinase 1/2, mediates Ca²⁺ influx-induced mitochondrial dysfunction, and inhibits the adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway in its absence. Besides, it enhances glucagon-like peptide-1 synthesis to maintain blood glucose levels and reduces dietary lipid absorption efficiency via calmodulin-dependent protein kinase II. ERK: Extracellular signal-regulated kinase; Me: Methyl group; SUV39h1-H3K9me3: Suppressor of variegation 3-9 homolog 1-histone H3 lysine 9 trimethylation; ROCK1/2: Rho-associated coiled-coil containing protein kinase 1/2; AMPK: Adenosine monophosphate-activated protein kinase; mTOR: Mechanistic target of rapamycin; GPX4: Glutathione peroxidase 4; GLP-1: Glucagon-like peptide-1; DGAT2: Diacylglycerol O-acyltransferase 2; CaMKII: Calmodulin-dependent protein kinase II; AMPKα: Adenosine monophosphate-activated protein kinase alpha subunit; CD36: Cluster of differentiation 36.

Piezo channels regulate IECs through multifaceted mechanisms: Tight junction proteins between IECs efficiently regulate intercellular gaps and serve as the key structural foundation determining intestinal permeability[32]. Piezo channels regulate the expression of tight junction proteins through distinct signaling pathways, thereby maintaining intestinal homeostasis. Research shows that Piezo1 can downregulate the expression of Claudin-1 through the Rho-associated coiled-coil containing protein kinase 1/2 (ROCK1/2) signaling pathway, which will destroy the integrity of the barrier and weaken the epithelial function[33]. At the same time, the inflow of Ca²⁺ triggered by Piezo1 activation will affect mitochondrial function, which will lead to damage to tightly connected proteins and induce apoptosis of epithelial cells[34]. In another case, when Piezo1 is absent, the AMPK/mechanistic target of rapamycin pathway is inhibited, the expression of glutathione peroxidase 4 increases, and the level of lipid peroxidation decreases accordingly. This process helps to maintain the stability of the tight connection[35]. There are differences between these results, which are often related to specific conditions. Short-term mechanical stimulation usually promotes changes in cell adaptability, while continuous accumulation of Ca²⁺ may cause mitochondrial damage and induce iron death. The analysis of this time-changing activation mode helps to provide a basis for targeted treatment. In addition to the effect on the tightly connected structure, Piezo1 can also sense the state of cell crowding and trigger live cell squeezing through the sheath amino alcohol-1-phosphate/ROCK signaling pathway, thus regulating the number of epithelial cells[36]. This mechanism ensures the prompt elimination of aging or damaged cells, thereby supporting the continuous renewal of barrier cells. Notably, while Piezo channels regulate the epithelial barrier, they also regulate nutrient absorption and systemic metabolic homeostasis. In the regulation of glucose metabolism, Piezo1 expression has been identified in L cells of the human and mouse small intestine. When Piezo1 is activated, it enhances the secretion of glucagon-like peptide-1, helping to maintain blood glucose homeostasis[37]. In lipid metabolism, the intestinal mechanical pressure generated by food intake activates the Piezo1 channel, inducing Ca²⁺ influx, which drives the phosphorylation of AMPKα (Thr172) via Calmodulin-dependent protein kinase II (CaMKII). Activated p-AMPKα directly binds to the diacylglycerol O-acyltransferase 2 gene promoter, inhibiting its transcription, while also downregulating the expression of the fatty acid transporter cluster of differentiation 36, reducing the expression of the triglyceride synthase diacylglycerol O-acyltransferase 2, and decreasing fatty acid uptake, ultimately reducing dietary lipid absorption efficiency[38] (Figure 1B). Therefore, in obesity, the functional deficiency of intestinal Piezo1 leads to an imbalance in this pathway, exacerbating systemic metabolic dysregulation. Activation of Piezo1 using the agonist Yoda1 can reportedly reverse the excessive absorption phenotype, offering a new therapeutic target for obesity intervention[38].

The role of Piezo in the multicellular regulation of immune defense: The intestinal immune barrier can recognize pathogens and foreign substances, produce antibodies and various cytokines, thereby regulating the immune response and maintaining intestinal homeostasis. Notably, Piezo channels play a critical regulatory role in immune responses and modulate the function of various immune cells. Macrophages are key effector cells of the intestinal innate immune system. They work synergistically with Piezo channels to regulate apoptosis and growth factor levels. These cells play a vital role in host anti-infection responses, resolving inflammation, and promoting intestinal mucosal repair[39]. Bacterial lipopolysaccharides can act on Toll-like receptor 4 on the surface of macrophages and induce Piezo1-mediated Ca²⁺ inflow. The calcium signal further regulates the skeletonal structure of F-actin cells through the Ca²⁺/CaMKII-Mst1/2-Rac1 pathway, thus enhancing the phagocytic function of macrophages and improving the ability to remove bacteria[40]. In addition, Piezo1 can regulate the Ca²⁺-CaMKII-HIF1α signaling axis, promoting the release of hypoxia-inducible factor 1α. This increases macrophage glycolytic activity and amplifies the inflammatory response[41] (Figure 2A). Notably, macrophages can sense microenvironmental stiffness through Piezo1 channels. On a rigid matrix, lipopolysaccharides enhances glycolysis and actin polymerization via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, exacerbating the inflammatory response. This process is closely linked with macrophage metabolic reprogramming. Increased matrix stiffness not only activates inflammatory signaling but also induces a glycolytic phenotype, which promotes macrophage activation and the production of pro-inflammatory cytokines, further reinforcing the inflammatory cycle[42]. Overall, these findings indicate that Piezo1 plays a critical role in linking mechanical cues to metabolic regulation within the inflammatory microenvironment. Targeting Piezo1 may provide a therapeutic approach to modulate macrophage polarization and inflammation.

Figure 2 Piezo regulates immune responses by coordinating macrophages and T/B cells. A: Piezo1 remodels F-actin via the Ca²⁺/calmodulin-dependent protein kinase II- mammalian sterile 20-like kinase 1/2-Ras-related C3 botulinum toxin substrate 1 signaling axis and enhances macrophage inflammation through calmodulin-dependent protein kinase II-hypoxia-inducible factor 1-alpha and nuclear factor kappa-light-chain-enhancer of activated B cells; B: When activated by localized membrane tension, Piezo1 induces Ca²⁺ influx, activating calcium-dependent proteases and promoting reorganization of the cortical actin cytoskeleton, thereby preventing excessive immune responses in T and B cells. LPS: Lipopolysaccharide; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; HIF-1α: Hypoxia-inducible factor 1-alpha; CaMKII: Calmodulin-dependent protein kinase II; Mst1/2: Mammalian sterile 20-like kinase 1/2; Rac1: Ras-related C3 botulinum toxin substrate 1; F-actin: Filamentous actin; DCs: Dendritic cells; ECs: Enterochromaffin cells; NK cells: Natural killer cells; T/B cells: T lymphocytes and B lymphocytes; TCR: T cell receptor; BCR: B cell receptor.

In the process of regulating the balance of T cell subgroups, T cell receptors will cause local changes in membrane tension after identifying antigens, which can activate the Piezo1 channel and trigger calcium ion inflow. Subsequently, calcium signals activate calcium-dependent protease and promote the reorganization of cortical actin cytoskeleton, thus improving the spatial distribution of T cell receptors signal conduction. The process helps to limit the excessive enhancement of the immune response[43]. A similar mechanism occurs in B cells, where Piezo1 activation upon B cell receptor recognition of membrane-bound antigens induces Ca²⁺ influx. This promotes immune synapse formation, as well as B cell proliferation and differentiation. Deletion or inhibition of Piezo1 significantly diminishes B cell responses to membrane-presented antigens[44], highlighting the essential role of Piezo1 in regulating humoral immunity (Figure 2B).

Dendritic cells (DCs) are professional antigen-presenting cells that sample environmental antigens and migrate to secondary lymphoid organs, acting as key sentinel cells in initiating adaptive immune responses[45]. Studies indicate that Piezo channels modulate DC function through multiple signaling pathways. When Piezo1 is activated by microenvironmental stiffness (≥ 50 kPa) or inflammatory stimuli, Ca²⁺ influx occurs, triggering the calcineurin-nuclear factor of activated T-cells pathway. This activates the sirtuin 1-hypoxia-inducible factor 1-alpha axis, enhancing glycolytic gene expression, promoting interleukin-12 production, expanding T helper type 1 cells, and reducing transforming growth factor β1 levels, thereby inhibiting regulatory T cell differentiation[46]. Under static mechanical tension (50 kPa), Piezo1 also cooperates with Hippo pathway effectors transcriptional co-activator with PDZ-binding motif/yes-associated protein to directly upregulate key glycolytic genes, reinforcing the innate immune phenotype of DCs[47] (Figure 3A). These results overlap in their assertion that Piezo1 plays a bridging role between mechanical signals and immune metabolic reprogramming.

Figure 3 Piezo regulates immune responses by coordinating dendritic cells, natural killer cells, and enterochromaffin cells. A: Piezo1 drives the activation of the calcium-dependent calcineurin-nuclear factor of activated T-cells pathway, activates the sirtuin 1-hypoxia-inducible factor 1-alpha axis to enhance glycolytic gene expression, promotes interleukin-12 production to amplify T helper type 1 cells, downregulates transforming growth factor β1 to inhibit regulatory T cell differentiation, and, in collaboration with the Hippo pathway effectors transcriptional co-activator with PDZ-binding motif/yes-associated protein, directly upregulates key glycolytic genes, thereby enhancing the innate immune phenotype of dendritic cells; B: Piezo1 reduces the killing efficiency of natural killer cells during tumor cell softening and shortens the killing time of natural killer cells during tumor cell hardening; C: Enterochromaffin cells sense mechanical forces through the Piezo2 channel. When Piezo2 is activated, it releases 5-hydroxytryptamine, which further activates enteric neurons, promotes intestinal fluid secretion, and maintains the oscillation of the transcription factor hairy and enhancer of split 1 through calcium signaling, thereby inhibiting intestinal inflammation. DCs: Dendritic cells; C-NFAT: Calcineurin nuclear factor of activated T-cells; TAZ: Transcriptional co-activator with PDZ-binding motif; YAP: Yes-associated protein; SIRT1: Sirtuin 1; HIF-1α: Hypoxia-inducible factor 1-alpha; IL-12: Interleukin 12; TGF-β1: Transforming growth factor β1; Th1: T helper type 1; Treg: Regulatory T cell; NK cells: Natural killer cells; ECs: Enterochromaffin cells; 5-HT: 5-hydroxytryptamine; Hes1: Hairy and enhancer of split 1.

Natural killer (NK) cells are lymphocytes that play an essential role in the innate and adaptive immune responses to tumors and viral infections[48]. Research has indicated that Piezo1 regulates the cytotoxic efficiency and infiltration ability of NK cells through mechanical sensing. A reduction in tumor cell stiffness correlates with a marked decrease in NK cell cytotoxic activity. This is marked by delayed release of lytic granules and reduced stability of the immune synapse. Notably, elevated tumor stiffness reduces the duration required for NK-mediated killing by nearly 40% and augments target-seeking migration via a Piezo1-Ca²⁺ signaling axis[49] (Figure 3B). This indicates that mechanical force sensing is a key regulator of NK cell effector functions.

Interestingly, IECs sense pathogen invasion via Piezo1, and during infection, the plasma membrane folds, triggering Ca²⁺ influx and ATP release, which activates the NF-κB signaling pathway to initiate the inflammatory response[50]. Although ECs account for less than 1% of IECs, they secrete about 90% of the body’s 5-hydroxytryptamine (5-HT), and are able to detect the gut microbiota and its metabolic products, activating both immune and neural pathways[51]. Piezo2 mechanosensitive channels play a key role in the mechanosensitivity of EC cells. Piezo2 protein expression has been observed in the human EC cell model QGP-1, where it co-localizes with 5-HT[52]. EC cells can harness Piezo2 channels to detect mechanical forces, regulating 5-HT secretion and maintaining the integrity of the mucosal immune barrier. When mechanical forces stimulate the intestinal lumen, Piezo2 channels are activated, generating a rapid inward ion current that increases intracellular Ca²⁺ levels, leading to the activation of EC cells to release 5-HT, which further activates intestinal neurons and enhances intestinal fluid secretion[53]. Besides, Piezo2 in EC cells regulates the oscillatory expression of the transcription factor Hes1 via calcium signaling, helping to suppress intestinal inflammation and maintain epithelial barrier integrity[54]. Inhibition of Piezo2 reduces 5-HT release in response to mechanical stimuli, impairing the gut’s ability to respond to mechanical forces and indirectly affecting neural signaling within the gut. This pathway may therefore represent a potential therapeutic target in disorders characterized by excessive 5-HT release[16] (Figure 3C).

Piezo’s bidirectional role in intestinal motility and mechanosensation

Intestinal motility and mechanosensation jointly constitute the core system that maintains homeostasis of digestion, excretion, and visceral perception. The regulatory process is mediated by the interaction between the intestinal nervous system and peripheral sensory neurons, and the two are in harmony. Piezo ion channels play a key role in it. They participate in regulation by sensing mechanical stimulation and mediating the release of neurotransmitters and the activation of sensory nerves. Between the epithelium and the nerve, these channels form an important signal connection point, which enables the effective transmission of mechanical signals.

Piezo1 serves as a key signaling hub in the gut, integrating mechanical and microbial cues. By sensing luminal microbial single-stranded RNA, Piezo1 promotes the transcription of tryptophan hydroxylase 1, the rate-limiting enzyme for 5-HT biosynthesis[55]. This suggests that Piezo1 may link microbial signals to the intestinal neural regulatory network, forming an intersecting “microbes mechanical neurotransmitters” pathway. Further studies have shown that activating Piezo1 with Yoda1 markedly inhibits synaptic growth and neuronal migration in enteric neurons, highlighting its potential as a therapeutic target for enteric neurodevelopmental disorders, such as congenital megacolon[48].

In difference, the Piezo2 channel in EC cells mainly mediates the inflow of Ca²⁺ caused by mechanical stimulation and promotes the release of 5-HT, and then the intestinal nervous system is activated, thus promoting intestinal peristalsis[56]. When Piezo2 is specifically knocked out in the epithelium, the overall passage time of the colon will be significantly prolonged[57], which indicates that the channel plays an important role in the process of peristalsis regulation. In the distal colon, mechanosensation is primarily mediated by dorsal root ganglion (DRG) neurons organized into threshold gradients. Piezo2 in DRG neurons is crucial for responding to high-intensity distension and inflammatory hyperalgesia, making it a key sensor of intestinal content tension[58]. Deletion of Piezo2 results in accelerated gastrointestinal transit, alternating diarrhea and constipation, and other defecation abnormalities. Colonic distension responses are abolished only in DRG-specific knockout models[8].

In the context of intestinal mechanosensation, Piezo2 is the central channel for DRG neurons in sensing colonic distension and plays a critical role in low-threshold mechanosensation. Knockout of Piezo2 can alleviate visceral hypersensitivity[59]. The release of 5-HT mediated by Piezo1/2 in EC cells communicates with neurons via 5-HT signaling, forming a rapid reflex pathway[60]. However, long-term inhibition of Piezo channels can activate the p38-tryptophan hydroxylase 1 pathway, leading to increased 5-HT synthesis and delayed intestinal transit efficiency, indicating the existence of a bidirectional feedback loop linking mechanosensation, serotonin synthesis, and intestinal motility[61].

In conclusion, Piezo channels exert multi-level regulatory functions in both intestinal motility and mechanosensation. On the one hand, Piezo channels promote intestinal motility by triggering rapid 5-HT release from ECs and modulate distension reflexes and visceral pain through sensory neurons. On the other hand, Piezo channels maintain normal motor rhythms under physiological conditions. However, abnormal activation or inhibition of Piezo channels can result in dysmotility and sensory dysfunction. This dual role positions Piezo as a central molecular hub connecting the mechanical environment, intercellular interactions, neural regulation, and the development of functional gastrointestinal disorders (Table 1).

Table 1 Multiple intestinal cell-mediated piezo channels and their effect mechanisms.

Cell types	Stimulation	Action mechanisms
Goblet cells	Mechanical stimulation	When Piezo1 is activated, it promotes the ERK/Ca2+ pathway[29] and inhibits the SUV39h1-H3K9me3 methylation pathway[30], promotes the secretion of mucin2, and maintains the intestinal mucus barrier
IECs	Mechanical stimulation	When Piezo1 is activated, it promotes ROCK1/2 pathway[33] and mediates Ca2+ inflow to induce mitochondrial dysfunction[34], inhibiting the expression of the closely connected protein Claudin-1, and weaking the intestinal epithelial barrier function
		When Piezo1 is absent, it inhibits the AMPK/mTOR pathway, upregulates GPX4 expression, and maintains the stability of tightly connected proteins[35]
	Cell crowding	Piezo1 can sense cell crowding and dynamically regulate the number of epithelial cells through the 1-phosphate/ROCK signaling pathway[36]
L cells	Blood glucose metabolism	When Piezo1 is activated, it can enhance GLP-1 secretion and maintain blood glucose homeostasis[37]
	Mechanical stimulation	When Piezo1 is activated, it inhibits DGAT2 gene promoter transcription, down-regulates the expression of CD36, reduces the expression of DGAT2 and fatty acid uptake, and reduces the efficiency of dietary lipid absorption[38]
		In the state of obesity, intestinal Piezo1 function deficiency aggravates lipid metabolism disorders[38]
Macrophages	Microbial stimulation	LPS activates TLR4 on the surface of macrophages, activates Piezo1 to reshape the F-actin skeleton structure through the Ca2+/CaMKII-Mst1/2-Rac1 signal axis, and enhances the ability of macrophages to engulf bacteria[40]
		When Piezo1 is activated, it promotes the release of HIF-1α through the Ca2+-CaMKII-HIF1α signal axis, enhances the glycolysis activity of macrophages, and amplifies the inflammatory response[41]
	The stiffness of the microenvironment	Under rigid matrix conditions, LPS perceives the rigidity of the microenvironment through the Piezo1 channel and aggravates the inflammatory reaction through the NF-κB pathway[42]
T/B cells	Changes in membrane tension	When Piezo1 is activated, it leads to Ca2+ inflow, promotes cortical actin skeleton reorganization, optimizes the spatial conformation of TCR signal transduction, and avoids excessive immune response[43]
		When Piezo1 is inhibited, the response of B cells to membrane presenting antigens is significantly reduced[44]
DCs	Microenvironment hardness (≥ 50 kPa) or inflammation	When Piezo1 is activated, Ca2+ flows inward, calcineurin-NFAT is activated, and the SIRT1-HIF1α axis enhances the expression of glycolysis genes, promotes IL-12 to amplify Th1 cells, and downregulates TGF-β1 to inhibit Tregs differentiation[46]
	Static mechanical tension (50 kPa)	When Piezo1 is activated, it cooperates with the Hippo pathway effect factor TAZ/YAP to upregulate the key glycolysis gene and enhance the DC inherent immune phenotype[47]
NK cells	Cell hardness	Piezo1 regulates the killing efficiency and infiltration ability of NK cells, reduces the killing efficiency of NK cells when tumor cells soften; when it hardens, it shortens the killing time of NK cells and accelerates the migration of NK cells[49]
ECs	Mechanical stimulation	When Piezo2 is activated, it releases 5-HT, activates intestinal neurons, promotes intestinal fluid secretion, and maintains transcription factor Hes1 vibration through calcium signals to inhibit intestinal inflammation[54]
		When Piezo2 is activated, it induces Ca2+ inflow and 5-HT release to promote intestinal peristalsis[56]
		Piezo inhibition can activate the p38-TPH1 pathway, increase 5-HT synthesis and slow down the efficiency of intestinal transmission[61]
Intestinal neurons	Microbial ssRNA	Piezo1 recognizes microbial ssRNA, upregulation of TPH1, and enhances 5-HT synthesis. Piezo1 activation can inhibit the synaptic growth and migration ability of intestinal neurons[55]
DRG neurons	Mechanical stimulation	When Piezo2 is activated, it promotes intestinal dilatation and perceived pain[58]

ERK: Extracellular signal-regulated kinase; SUV39h1: Suppressor of variegation 3-9 homolog 1; IECs: Intestinal epithelial cells; ROCK1/2: Rho-associated coiled-coil containing protein kinase1/2; AMPK: Adenosine 5’-monophosphate-activated protein kinase; mTOR: Mechanistic target of rapamycin; GPX4: Glutathione peroxidase 4; GLP-1: Glucagon-like peptide-1; DGAT2: Diacylglycerol O-acyltransferase 2; CD36: Cluster of differentiation 36; LPS: Lipopolysaccharide; TLR4: Toll-like receptor 4; CaMKII: Calmodulin-dependent protein kinase II; Mst1/2: Mammalian sterile 20-like kinase 1/2; Rac1: Ras-related C3 botulinum toxin substrate 1; HIF-1α: Hypoxia-inducible factor 1-alpha; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; TCR: T cell receptor; DCs: Dendritic cells; NFAT: Nuclear factor of activated T cells; SIRT1: Sirtuin 1; IL-12: Interleukin-12; Th1: Type 1 helper T cell; TGF-β: Transforming growth factor β1; Tregs: Regulatory T cells; TAZ/YAP: Transcriptional coactivator with PDZ-binding motif/yes-associated protein; NK cells: Natural killer; ECs: Enterochromaffin cells; 5-HT: 5-Hydroxytryptamine; TPH1: Tryptophan hydroxylase 1; ssRNA: Single-stranded RNA; Hes1: Hairy and enhancer of split 1; DRG: Dorsal root ganglion.

PATHOLOGICAL ROLE AND INTERVENTION POTENTIAL OF PIEZO CHANNELS IN INTESTINAL DISEASES

In the field of intestinal research, studies have shown that Piezo channels play a role in the pathogenesis of benign gastrointestinal diseases such as IBD, IBS, and malignant conditions such as colon cancer through various mechanisms, making it a key molecular player in intestinal mechanosensation[62].

IBD

IBD is a chronic intestinal inflammatory disease, mainly including two types: Crohn’s disease and ulcerative colitis. Epidemiological surveys show that the incidence and prevalence of IBD are on the rise worldwide[63]. Patients with IBD present with a wide range of recurring clinical symptoms. These symptoms include gastrointestinal complaints such as abdominal pain, diarrhea, and bleeding, as well as chronic inflammation, complications, and extra-intestinal manifestations, which will significantly affect the overall health of patients[64]. The pathogenesis of IBD primarily involves mucosal immune dysregulation[65], gut microbiota disturbances[66], and the interplay of genetic and environmental factors[67]. In recent years, aberrant mechanotransduction has been increasingly recognized as a key factor in the pathogenesis of IBD. Piezo channels are now considered critical molecular hubs in this process (Table 2).

Table 2 Pathogenic mechanisms of piezo channel in inflammatory bowel disease.

Pathogenic mechanism	Related pathways	Specific effect
Inflammatory regulation	Elevated expression of Piezo1 induces Ca2+ influx in HT29 cells, leading to ROS accumulation and activation of NLRP3 inflammasome[14]	Intestinal inflammation worsens; impaired intestinal barrier function; worsening of oxidative stress injury in intestinal epithelium
	Piezo1 regulates aerobic glycolysis in macrophages and enhances LPS-induced immune responses. Additionally, Piezo1 can increase the levels of IL-6, TNF-α, and IL-1β[43]	The pro-inflammatory immune response of macrophages is exacerbated; increased secretion of inflammatory cytokines
	In IECs, Piezo1 activation induces Ca2+ influx and leads to ATP secretion, promoting the secretion of immune factors such as IL-8, and regulates modulatory genes in immune pathways[52]	Disruption of immune pathway regulation exacerbates inflammatory responses
Immunodeficiency	The absence of Piezo1 promotes the polarization of Th1 and Th17 cells, leading to reduced inflammatory signaling[70]	Pathogenic T-cell inflammatory response is attenuated, alleviating inflammation

ROS: Reactive oxygen species; LPS: Lipopolysaccharide; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor alpha; IL-1β: Interleukin-1β; IECs: Intestinal epithelial cells; IL-8: Interleukin-8; Th1: Type 1 helper T cell; Th17: T helper 17 cells.

Growing evidence underscores the role of Piezo channels in IBD, and targeting them for therapy holds great significance. Among them, the use of Piezo inhibitor grammostola spatulata mechanosensitive channel toxin 4 (GsMTx4) has emerged as a research hotspot. GsMTx4 is a 35-amino acid peptide toxin isolated from spider venom[68]. This substance influences channel gating function by altering the membrane tension, rather than directly blocking the channel pores[69]. Its distinct conformation provides strong resistance to gastrointestinal enzyme degradation, offering potential benefits in oral drug treatment for ion channel-related diseases[70]. Additionally, the inhibition of Piezo channels by GsMTx4 is reversible and voltage-insensitive[68]. Research indicates that GsMTx4, as a Piezo channel inhibitor, can alleviate inflammation caused by excessive mechanical stimulation by inhibiting Piezo channel activity. As an immune-mediated disease, abnormal Ca²⁺ signaling in IBD can amplify the inflammatory cascade, and GsMTx4 helps improve the inflammatory state by regulating Ca²⁺ influx[69]. Inhibition of Piezo1 in dextran sulfate sodium-induced colitis models has been shown to regulate group 3 innate lymphoid cell proliferation and interleukin-17A secretion, leading to a marked reduction in inflammatory pathology[71]. Besides, GsMTx4 can regulate the stearoyl-CoA desaturase 1-mediated fatty acid desaturation process by inhibiting Piezo1, repair the impaired stem cell function in colitis, and preserve intestinal barrier integrity[33]. Modulation of Piezo channels may act higher in the signaling hierarchy than cytokine-directed biologics (e.g., anti-tumor necrosis factor, anti-interleukin-23), especially in the key link of mechanical signal transduction. However, whether this approach offers additive or synergistic benefits remains to be determined. These findings collectively indicate that excessive activation of Piezo channels may promote chronic inflammation, and the use of drug-targeted inhibition of Piezo channels is expected to open up a new strategic direction for IBD treatment.

IBS

IBS is a chronic functional gastrointestinal disease, the main manifestations of which are abdominal pain and changes in bowel habits[72]. This kind of disease affects about 11% of the world’s population, which not only significantly reduces the quality of life of patients, but also brings a huge socio-economic burden[73]. The pathogenesis of IBS is multifactorial, involving the interaction of factors such as brain-gut axis dysregulation[74], visceral hypersensitivity[75], intestinal barrier dysfunction[76], and gut microbiota imbalance[77]. In recent years, Piezo channels have been recognized as crucial participants in the pathophysiology of IBS, owing to their pivotal roles in mechanosensation and neural regulation (Table 3)[78-89].

Table 3 Pathogenic mechanisms of piezo in irritable bowel syndrome.

Pathogenic mechanism	Related pathways	Specific effect
Intestinal barrier disruption	Mechanical stimulation induces upregulation of Piezo1, activates ROCK1/2, and inhibits claudin1 expression[33]	The abnormal increase in intestinal epithelial permeability and impaired barrier function exacerbates the intestinal inflammatory response
	Activation of goblet cell Piezo1, inhibition of SUV39h1, downregulation of H3K9me3, and upregulation of mucin2 transcription[30]	Alteration of intestinal flora; abnormal mucus secretion and impaired barrier function
Visceral hypersensitivity	Mechanical stimulation activates EC cells Piezo2, releasing 5-HT, which activates 5-HT3 receptors in sensory nerves to transmit nociceptive signals[53,57,78-80]	Acute and persistent pain
	Pathological stimulation of DRG neurons leads to Piezo2 activation, Ca2+ influx, enhanced CREB/Akt signaling, and promotion of CGRP release[15,59,81]	Spinal cord central sensitization causes mild mechanical stimuli to be perceived as pain, which further progresses into chronic persistent visceral pain
	Piezo2 is expressed in the TRPV1 family of nociceptors in the colon, responding to mechanical distension[15,82-85]	Pathomechanical hyperalgesia
Neuroendocrine dysfunction	Piezo2 detects mechanical stimuli, which stimulate EC cells to release increased 5-HT, leading to the corresponding symptoms of IBS[86-89]	Intermittent abdominal pain and abdominal distension; alternating diarrhea and constipation
	Piezo2 detects mechanical stimuli, which stimulate EC cells to release increased 5-HT, leading to serotonin signaling dysfunction in the gut-brain axis[78,86]	Abnormal intestinal-brain interaction; extraintestinal symptoms such as psychiatric disorders

ROCK1/2: Rho-associated coiled-coil containing protein kinase 1/2; SUV39h1: Suppressor of variegation 3-9 homolog 1; ECs: Enterochromaffin cells; 5-HT: 5-hydroxytryptamine; DRG: Dorsal root ganglion; CREB: CAMP-response element binding protein; Akt: Protein kinase B; CGRP: Calcitonin gene-related peptide; TRPV1: Transient receptor potential vanilloid 1; IBS: Irritable bowel syndrome.

Therefore, detecting the expression levels of Piezo1/2 may assist in the clinical diagnosis of IBS. In a mouse model of Trichinella infection, colonic Piezo2 expression was significantly increased compared to healthy controls and strongly correlated with visceral hypersensitivity, suggesting it as a potential biomarker for IBS-related visceral hypersensitivity[17]. Electroacupuncture stimulation in the IBS mouse model significantly reduced visceral hypersensitivity. This effect may be linked to the downregulation of the Epac1-Piezo2 axis activity in the colon and L5-S2 DRG, along with a decrease in 5-HT and its receptor 5-HT3R expression[90]. Deleting Piezo2 from sensory neurons shortened intestinal transit time, increased stool frequency, and elevated stool water content, accelerating the passage of food through the gastrointestinal tract[77]. Similarly, the use of the Piezo channel inhibitor GsMTx4, which reversibly inhibits Piezo1/2 channels, increases 5-HT secretion in QGP-1 cells and activates the p38 MAPK signaling pathway, thereby directly delaying intestinal transit efficiency. This contributes to the restoration of normal intestinal motility and alleviates symptoms in IBS patients[61]. Thus, further investigation into the specific mechanisms of Piezo channels in IBS could aid the development of new therapeutic strategies.

Colon cancer

Accounting for roughly 10% of all cases, colon cancer is one of the leading causes of cancer-related death worldwide, ranking third in both global incidence and mortality[91]. In addition to symptoms such as intestinal dysfunction, bloody stool, abdominal pain and weight loss, bone and visceral muscle atrophy may occur in the late stages of the disease, and its development involves multiple molecular and microenvironmental factors. The pathogenic mechanisms are diverse, and research indicates that Piezo channels contribute to tumor metastasis, invasion, and progression (Table 4)[92-95].

Table 4 Pathogenic mechanisms of piezo in colon cancer.

Pathogenic mechanism	Related pathways	Specific effect
Tumor promotion	Piezo1 gene functional mutation increases cancer risk[92]	Promotes the transformation of normal mucosal epithelium into adenoma and accelerates the malignant progression from adenoma to carcinoma
Tumor proliferation and metastasis	Piezo2 drives the proliferation, migration, and angiogenesis of colon cancer cells by activating the SLIT2/ROBO1 pathway, which upregulates HIF-1α/VEGFC, and collaborates with CAFs to shape the pro-oncogenic microenvironment[93]	Accelerated tumor progression, significantly increased rates of lymph node metastasis and distant metastasis risk, and decreased overall patient survival rate
	Piezo1 induces EMT and angiogenesis by activating the Ca2+ influx/HIF-1α/VEGF signaling axis[94]	Tumor cell proliferation and migration
Tumor immune evasion	Piezo1 activation downregulates MCU, upregulates HIF-1α and VEGF, disrupts mitochondrial function, and promotes cancer cell metastasis[92]	Enhances tumor cell proliferation and migration, resulting in poor patient prognosis
	By regulating Piezo1 to influence Ca2+ levels, activate or degrade NFAT1, and maintain the stem cell characteristics of colon cancer[95]	Tumor development and immune evasion

SLIT2: Slit homolog 2; ROBO1: Roundabout homolog 1; HIF-1α: Hypoxia-inducible factor 1-alpha; VEGFC: Vascular endothelial growth factor C; CAFs: Cancer-associated fibroblasts; EMT: Epithelial-mesenchymal transition; VEGF: Vascular endothelial growth factor; MCU: Mitochondrial calcium uniporter; NFAT1 Nuclear factor of activated T-cells 1.

Further investigation on the role of Piezo channels in targeted treatment for colon cancer reveals a significant association between abnormal Piezo expression and poor prognosis in digestive tumors, indicating that Piezo channels could serve as potential prognostic biomarkers for cancer[96]. In vivo studies, Piezo1 deficiency significantly restricts tumor volume and growth in nude mouse subcutaneous xenografts while promoting the expression of pro-apoptotic factors[97]. Similarly, the absence of Piezo1 also impairs the migration and invasion ability of tumor cells[98].

It is worth noting that the systemic influence of Piezo channels extends beyond the intestine. In the stomach, these channels can regulate satiety[99] and the tumor metastasis process[94,100]. In the liver, Piezo channels become key hubs in liver pathological processes by regulating tumors[101,102], driving liver fibrosis[103], facilitating portal hypertension[104,105] and orchestrating immune microenvironment remodeling[106]. In the pancreas, these channels maintain metabolic stability on the one hand, and on the other hand, they also affect the course of the disease by mediating the occurrence of pancreatitis[107,108], ensuring the integrity of vascular structure[109] and regulating insulin secretion of beta cells[110,111]. Overall, the Piezo channel plays a cross-system regulatory role in inflammation, functional diseases and tumor progression. If its specific regulatory mechanism can be deeply analyzed, it will provide new ideas for the treatment of these diseases.

CONCLUSION

Piezo channel plays a central role in regulating intestinal homeostasis, which is comprehensively explained in this article. As a highly conservative mechanically sensitive ion channel, Piezo can convert constant tension, pressure, and shear stress within the intestinal lumen into Ca²⁺-dependent signaling cascades. These cascade reactions can activate key pathways such as ROCK, hypoxia-inducible factor 1α, and NF-κB, thus forming a mechanical biological network. Through this network, the renewal of epithelial cells, the maintenance of barrier function, immune regulation and nerve reflexes are integrated together. At the homeostatic level of the intestinal barrier, Piezo1 relies on the inflow of calcium ions to promote the proliferation and differentiation of ISCs. This process lays the foundation for the construction of epithelial structure. Meanwhile, Piezo1 is also responsible for coordinating the activities of macrophages, DCs and NK cells in mucosal immunity. For the regulation of intestinal movement, the Piezo2 channel in intestinal pheochromocytes plays a role in maintaining a positive feedback cycle, which drives the progress of peristalsis and the feedback of sensory signals. Once the function of the Piezo channel is disturbed, it will directly promote the pathological process of IBD, IBS and colon cancer. In terms of therapeutic intervention, drug tools such as Yoda1 and GsMTx4 have shown the initial clinical application value of targeting Piezo channels. In addition to chemical drugs, physical stimulation has also been proven to be an effective means of regulation. In recent years, the research on gene editing, targeted delivery and signal intervention for Piezo channels has gradually become a new direction for the diagnosis and treatment of intestinal diseases. Piezo related research is being pushed from basic discovery to practical application of precision medicine.

However, there are significant challenges in translating findings from animal models to human diseases. Notably, piezoelectric channels are widely expressed in human tissues[112-114], and systemic activation or inhibition may lead to off-target effects and adverse outcomes. Relevant studies have demonstrated that piezoelectric channels contribute to myocardial hypertrophy. Importantly, systemic inhibition of these channels may disrupt normal cardiovascular blood flow pressure sensing and vascular tension regulation[115]. Furthermore, systemic intervention targeting piezoelectric channels may exert irreversible effects on normal neural function and the cell cycle[113]. Besides, most current evidence comes from animal models or cell-based experiments, while human tissue samples and clinical cohort studies are relatively scarce, and their relevance warrants further investigation and validation. Given the aforementioned limitations, future research could focus on the following directions: First, this study involved the development of a “mechanical-genetic” map of the human intestine; identifying potentially pathogenic Piezo mutations through large-scale cohort analysis[21], and combining CRISPR editing with organoid models to simulate pathological mechanical microenvironments. Besides, the functional coupling between Piezo and other mechanosensitive channels such as TRP vanilloid 4 was explored, and targeted delivery systems for specific cell types (such as EC cells or macrophages) were developed to enable precise interventions, while considering potential off-target effects of GsMTx4[52]. Third, drug metabolism and local delivery strategies were optimized to minimize potential side effects on non-target organs, thus accelerating clinical application. Piezo channel research is promoting the transformation of intestinal disease-related thinking, that is, the transition from a traditional inflammation model to a multi-dimensional mechanical transduction framework. These understandings from mechanical biology provide a basis for accurate diagnosis and patient stratification. This also indicates that the clinical management of these diseases will undergo a major adjustment in the future.