PIEZO1-mediated Perception of Intestinal Mechanical Forces and Metabolic Regulation: Recent Advances from Structure to Function

Abstract

PIEZO1, a representative member of mechanosensitive ion channels, plays crucial roles in various physiological and pathological processes. This review focuses on significant advances regarding the role of PIEZO1 in intestinal mechanical signal transduction and metabolic regulation since 2022. Recent studies have elucidated structural characteristics of PIEZO1 and how its conformational changes mediate mechanical signal transduction. PIEZO1 exhibits specific distribution patterns in the intestinal environment and preferentially responds to high-intensity mechanical stresses while maintaining functional stability. From a signal transduction perspective, PIEZO1 activation triggers multiple downstream pathways through calcium influx, regulating inflammatory responses, cell apoptosis, tissue repair, and metabolism. These multi-level regulatory mechanisms provide new insights into understanding intestinal mechanosensing and metabolism-related diseases while establishing a theoretical foundation for developing PIEZO1-targeted therapeutic strategies.

Graphical abstract

Keywords

PIEZO1 / intestinal mechanical signal transduction / calcium influx / metabolic regulation / therapeutic strategies

Introduction

Mechanical signal transduction, the process by which mechanical stresses such as static pressure, stretch stress, and shear stress are transformed into electrochemical signals, underlies a variety of (patho) physiological processes[1–3]. The primary mechanism of mechanical signal transduction was determined with the identification of mechanosensitive ion channels[4]. Of these, PIEZO1 protein is a nonselective, converted mechanosensitive ion channel that was identified in 2010[5]. PIEZO1 is ubiquitously expressed through the gastrointestinal (GI) tract[6]. Growing evidence suggests that it is critical for the occurrence and progression of numerous GI diseases such as inflammatory bowel disease[7], irritable bowel syndrome[8] and colon cancer[9]. Its importance for treating GI diseases has made it a research hotspot in recent years. This review focuses on significant developments in PIEZO1-related intestinal mechanical signal transduction and PIEZO1-targeted therapeutic strategies since 2022 (Figure 1). It aims to elucidate the regulatory role of PIEZO1 in intestinal health and disease and to provide a theoretical basis for the diagnosis and treatment of related diseases.

Structure-function correlation of PIEZO1

PIEZO1 is a large membrane protein with 24–36 transmembrane domains, which does not belong to any known ion channel family[5]. As illustrated in (Figure 2), It forms a three-bladed, propeller-shaped homotrimeric structure comprising three peripheral mechanosensing blades and a central ion-conducting pore[10–13]. Multiple studies have identified the central ion-conducting pore and the three peripheral propeller-like blades as the two critical regions for PIEZO1 function as a mechanosensitive channel[14,15]. As technology advances, the understanding of the structure of this channel continues to deepen.

The structural plasticity and intrinsic curvature of the PIEZO1 channel are now widely accepted as key features. The blade, beam and cap structure of PIEZO1 is highly flexible. When membrane tension is applied, these structures undergo deformation, such as flattening of the blade, bending of the beam, and rotation and separation of the cap structure, which directly leads to the expansion of the central ion pore and the conversion of mechanical force into an electrical signal[16]. Changes in PIEZO1 conformation directly correspond to the functional state of the channel. This structure-function correlation is reflected in three main conformational states: the resting state adopts a highly bent conformation with all channels closed; the partially flattened state represents the conducting state, where the upper valve rotates to widen the entrance, while compression of the elastic link segment triggers the opening of the transmembrane channel, forming an ion pathway, though the lateral plug remains in place; and the entirely flattened conformation shows the upper valve returning to its original position and closing. Although the transmembrane channel remains partially expanded, it is no longer conductive, reflecting the inactivated state of the channel[17]. At the microscopic level, nanofluorescence imaging was used to show that bending stress in the resting cell membrane led to a substantial expansion of PIEZO1’s blade structure, with the degree of expansion positively correlated with channel activation[18].Using single-channel patch-clamp techniques, it has been found that PIEZO1 has two subconductance states, approximately 1/3 and 2/3 of the fully open conductance. These sub-conductance states are intrinsic properties of the channel. They can be observed even when PIEZO1 is reconstituted in liposomes containing only lipids, indicating that they are not dependent on complex regulatory factors in the cell environment[19]. The above studies have collectively elucidated the conformational changes between the open and closed states of PIEZO1 and how it transduces mechanical signals in response to membrane tension.

Regarding functional regulation, there are multiple splicing isoforms of PIEZO1. The long isoform (CIOCS1g) can rescue the mutant phenotype, whereas the short isoform (CIOCS1l) cannot restore channel function, indicating functional differentiation between isoforms. Different splice variants may exhibit distinct functional properties in various intestinal cells and regions[20]. In addition to splice variant regulation, protein-protein interactions are an essential mechanism for regulating the function of PIEZO1. The MyoD family inhibitory proteins (MDFIC/MDFI) may enhance the persistence of downstream signalling pathways by stabilizing the binding to the pore module of the PIEZO channel and delaying its inactivation. This could potentially prolong the duration of ion currents triggered by mechanical stimuli[21]. Phosphatidylinositol is a membrane phospholipid that is often essential for membrane protein function, and depletion of PI (4,5) P₂ decreases PIEZO1 currents. The lipid composition of intestinal epithelial cell membranes may regulate PIEZO1 activity, influencing its response to mechanical stimuli and metabolism-related signalling[22]. These findings at the gene, protein and membrane environment levels provide a molecular theoretical foundation for understanding the complexity of the PIEZO1 channel.

Taken together, PIEZO1 channel presents dual characteristics of autonomy and complexity. Although structural research has greatly enhanced our understanding of how PIEZO1 functions as a mechanosensitive ion channel, the precise mechanosensory gating mechanisms of PIEZO1, the detailed functions of certain structural domains, and the regulatory differences across various tissue types remain essential directions for future research.

PIEZO1 in the transduction of intestinal mechanical signals as a mechanically sensitive ion channel

PIEZO1 is widely expressed in various cell types. It plays a key role in tissues that experience significant mechanical forces, such as the GI tract[23]. This article focuses on how PIEZO1 affects the gut.

At the molecular functional level, PIEZO1 in the intestine may respond to mechanical stimuli in a graded manner through different subconductance states, thereby modulating the efficiency and specificity of mechanotransduction[19]. The functional differences between different PIEZO1 splice variants may reflect their adaptive regulatory mechanisms for tissue-specific mechanical signals. The specific distribution and functional differences of PIEZO1 splice variants across different intestinal segments and cell types remain topics that require further in-depth exploration[20].

At the cellular level, recent studies have shown that cells expressing PIEZO1 have the highest threshold for detecting mechanical stimuli compared to other mechanically sensitive ion channels[24]. This suggests that in the gut, PIEZO1 may respond preferentially to high-intensity mechanical stimuli, such as the continuous stretch caused by the passage of a food bolus, rather than to small changes in pressure. Interestingly, disruption of the cytoskeleton does not affect the mechanical detection threshold of PIEZO1-mediated mechanosensitivity. This functional autonomy of PIEZO1 likely enables stable mechanosensing in intestinal cells, making it resistant to interference from dynamic cytoskeletal remodelling that occurs during structural changes associated with intestinal peristalsis. The insensitivity of PIEZO1 to changes in the cytoskeleton may ensure that PIEZO1 stably detects high-intensity signals in the complex mechanical environment of the intestine. At the cellular structural level, microvilli of intestinal epithelial cells may regulate PIEZO1 distribution through membrane curvature-dependent sorting mechanisms. PIEZO1 preferentially accumulates in low-curvature regions at the base of microvilli, where it responds explicitly to high-magnitude tensile forces generated by chyme flow, thereby contributing to the regulation of nutrient absorption and epithelial barrier function[25].

At the whole-intestine level, studies indicate that PIEZO1 channels regulate food movement through the intestine in the C. elegans model when food boluses accumulate[20,26]. The specific mechanism involves PIEZO1 sensing distension in the anterior intestine caused by food accumulation, which activates downstream calcium signalling pathways. This signal is transmitted to the head region, triggering head/neck muscle contraction that drives the pharyngeal plunge phenomenon. This movement pattern facilitates food transit from the anterior to the posterior intestine, allowing the worm’s digestive tract to dynamically adjust its digestive rhythm based on the amount of accumulated intestinal contents[20]. Although this mechanism has been confirmed in the nematode model, the basic principle it reveals has cross-species significance. Building on the findings in the nematode model, studies in mammals have further advanced our understanding of the role of PIEZO1 in the enteric nervous system. A recent study demonstrated that in a mouse model, cholinergic neurons in the enteric nervous system can directly sense luminal pressure through PIEZO1, thereby regulating intestinal motility and maintaining immune homeostasis[23]. This finding suggests that PIEZO1-mediated mechanosensation is evolutionarily conserved but has acquired more complex regulatory functions in mammals. The fundamental mechanisms discovered in C. elegans and mice provide valuable insights for understanding mechanosensing mechanisms in the human intestine.

These mechanisms ensure the precise perception of intestine and appropriate response to mechanical stimuli. They provide potential targets for mechanistic research and treating diseases associated with intestinal dysfunction.

The signaling pathway after activation of the intestinal PIEZO1 basic mechanisms and calcium signaling of PIEZO1

PIEZO1 acts as an upstream regulator of calcium-dependent signalling pathways, and its activation can directly respond to mechanical stimuli such as shear stress to regulate calcium influx. After the knockdown of PIEZO1 expression by siRNA, shear stress-induced calcium influx was significantly reduced, whereas the control group maintained higher levels of calcium influx[27]. Activation of PIEZO1 promotes Ca²⁺ influx, which triggers several downstream signalling pathways[27–31]. In the vascular system, PIEZO1-Ca²⁺ signalling can activate the CaMKII/eNOS pathway to regulate vascular function, affect the PI3K/Akt pathway through intermediary molecules such as Dkk3 to participate in cell survival and metabolism, and directly activate MT1-MMP to join in the angiogenesis process. Recent studies have shown that PIEZO1-mediated Ca²⁺ signalling in the intestine can regulate the inflammatory response through the PI3K/Akt pathway[32]. In terms of intestinal function, numerous evidences have confimed that mechanical pressure from the contents of the intestine can be sensed by PIEZO1, triggering an influx of calcium, which in turn regulates the secretion of hormones such as GLP-1 or the transport of nutrients by endocrine cells in the intestine[22,25]. The potential role of other PIEZO1-related signalling pathways in regulating intestinal function remains to be explored in depth. This represents a new line of research for understanding the relationship between intestinal mechanosensing and metabolic regulation.

PIEZO1-mediated mechanosensation and inflammatory signal mechanisms

Iron death is caused by increased membrane tension induced by lipid peroxidation, which selectively activates the mechanically sensitive channel PIEZO1. This process disrupts ion homeostasis by mediating inward Na⁺ or outward K⁺ flux and is independent of the production of lipid peroxidation products[33]. This finding reveals how PIEZO1 responds to changes in membrane physical properties and establishes a foundation for understanding its role in various physiological and pathological processes. It has been confirmed that PIEZO1 directly regulates TWIK-related potassium channel 1 (TREK1) channels through conformational changes rather than ion permeation, using chemical restriction of PIEZO1 conformational flexibility and super-resolution imaging[34]. The two channels do not bind directly, but most TREK1 is located within the PIEZO1 membrane footprint at high densities, suggesting that the membrane footprint mediates conformational signalling. These results indicate that PIEZO1 may coordinate metabolic responses in mechanically sensitive tissues, such as the intestine, through dual ion flow-dependent and -independent pathways. For example, intestinal luminal pressure may directly activate adjacent metabolic proteins through conformational signalling, while calcium signalling may be involved in other coordinated regulations.

Based on the above-mentioned related signal transduction mechanism mediated by PIEZO1, PIEZO1 is involved in multiple inflammatory signalling cascades by sensing mechanical forces. When PIEZO1 is activated by mechanical force, it drives NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome assembly and cytokine release through the IKKβ-NF-κB pathway. on the other hand, the calcium influx mediated by it provides a second signal for NLRP3 inflammasome activation, synergistically converting physical stimuli into an inflammatory response[35,36]. Studies have shown that mechanical stimulation activates potassium calcium-activated channel subfamily N member 4 (KCNN4) channels through calcium influx mediated by PIEZO1, inducing potassium efflux and enhancing activation of the NLRP3 inflammasome[37]. This mechanism has been shown to amplify the inflammatory response in immune cells. These findings establish the mechanism by which the PIEZO1-KCNN4-NLRP3 signalling axis mediates the conversion of mechanical stimuli into an inflammatory response in macrophages. However, the role of this pathway in intestinal inflammation, particularly metabolic enteritis, remains a significant research gap.

This inflammatory activation mechanism triggers several downstream effects. Mechanical forces can induce NLRP3 inflammasome activation via PIEZO1, and thus leading to Gasdermin D-dependent cell death[38]. In addition to the classical inflammatory pathway, PIEZO1-dependent mechanical signals can specifically activate atypical NF-κB pathways, such as the p52/p65 heterodimer[36]. These pathways are distinct from the traditional TLR4 pathway and may be involved in tissue-specific inflammatory regulation. These atypical pathways have attracted attention, but their specific contribution to related diseases is not fully understood.

Notably, microenvironmental factors play an essential regulatory role in PIEZO1-mediated inflammatory responses. Importantly, microenvironmental factors play a crucial role in regulating PIEZO1-mediated inflammatory reactions. Cell-cell contact may enhance PIEZO1-mediated mechanical force responses through paracrine signals such as ATP release, suggesting that the environment of densely arranged intestinal epithelial cells may be more likely to trigger an inflammatory cascade[36]. This microenvironmental dependency extends to the immune system level. PIEZO1 is involved in intestinal inflammatory responses by regulating the function of immune cells such as CD4⁺ T cells, which may affect the immune microenvironment related to metabolism[39].

These findings provide new insights into the role of PIEZO1 in metabolic diseases. However, the precise tissue-specific regulatory mechanisms remain to be fully elucidated.

The dual role of PIEZO1 in apoptosis and tissue repair

PIEZO1 plays a complex role in the regulation of apoptosis. On the one hand, its regular expression maintains cell survival, while on the other hand, it can induce apoptosis under certain conditions. PIEZO1 regulates apoptosis through the p53/Bax/caspase-3 signaling axis. Knockdown of PIEZO1 can induce apoptosis, and it is speculated that deletion of PIEZO1 may activate pro-apoptotic pathways[26]. In invertebrate model studies, failure of chromosome association in nematode oocytes causes retention of polo‑like kinase 2 (PLK-2) kinase at pairing centres. This subsequently leads to nuclear laminin (LMN-1) phosphorylation, which reduces nuclear envelope stability. Deformation of the nuclear envelope activates PIEZO1 channels localized on the nuclear membrane, ultimately triggering apoptosis[40]. There is no evidence that this nuclear membrane-associated PIEZO1 activation mechanism exists in the mammalian intestine. Given the evolutionary conservation of the mechanosensory pathway, this finding provides insight into understanding the metabolic stress response in mammals in which PIEZO1 may be involved, such as intestinal stem cell clearance. However, this hypothesis must be verified by confirming PIEZO1’s nuclear membrane localization and the mechanosensory-metabolic signal coupling pathway in mammals.

PIEZO1 also plays a vital role in tissue repair. Studies have shown that extracellular matrix components have a regulatory effect on PIEZO1 function. Fibronectin (FN) may increase the sensitivity of PIEZO1 to mechanical stimuli[28]. PIEZO1 maintains intestinal epithelial homeostasis by sensing mechanical signals, directly affecting cell renewal and tissue repair. Specifically, PIEZO1 directly affects mucus synthesis and secretion by regulating goblet cell mechanical sensing. Previous experimental studies have shown that in a mouse model with the specific knockout of PIEZO1 in intestinal goblet cells, the mucus layer is significantly thinned, the intestinal barrier defence function is disrupted, and the number of pathogenic bacteria in the intestine increases, ultimately leading to an increase in colonisation by pathogenic microorganisms accompanied by an increase in levels of inflammatory factors[39,41].

These studies indicate that PIEZO1 plays a key regulatory role in apoptosis and tissue repair by sensing and transducing mechanical signals. Its bidirectional action provides a new perspective for understanding the mechanism of intestinal epithelial homeostasis maintenance and developing related disease intervention strategies.

Regulation of metabolism and secretion of hormones

The mechanosensitive channel PIEZO1 converts physical signals from glucose metabolism into biochemical signals for insulin secretion. For example, glucose-induced changes in cell volume and membrane deformation activate PIEZO1, which promotes insulin release by pancreatic β-cells[39]. Activation of PIEZO1 in intestinal cells may regulate the dynamics of microvilli through structural changes, thereby altering cell surface area and absorption efficiency. This process is directly related to nutrient absorption and metabolism[25]. These early observations established the foundation for understanding the role of PIEZO1 in metabolic regulation, while recent studies have provided more direct molecular mechanistic evidence. PIEZO1 has been shown to negatively regulate the expression of DGAT2 and SGLT1 through the CaMKK2-AMPK pathway, thereby inhibiting intestinal absorption of lipids and sugars. Notably, this mechanism is dysregulated in obesity, as evidenced by decreased PIEZO1 expression and activity, leading to intestinal absorption dysfunction[42]. This finding reveals how the perception of mechanical forces in the intestine is directly involved in the fine regulation of nutrient absorption. It provides a crucial mechanistic basis for understanding the role of PIEZO1 in metabolic diseases associated with intestinal dysfunction.

Therapeutic strategies targeting PIEZO1

Given that PIEZO1 plays critical roles in GI motility and intestinal epithelial barrier repair, targeting this mechanosensitive protein has emerged as a new strategy for the treatment of digestive diseases. Current PIEZO1 modulators can be classified into two functional categories, agonists and inhibitors, including synthetic small molecules, peptide toxins, and natural compounds. Yoda1 is the first selective PIEZO1 agonist. It enhances Ca²⁺ influx by lowering the channel’s mechanical activation threshold and delaying its inactivation[43]. It has been widely used to dissect PIEZO1-dependent signaling in intestinal homeostasis, although its poor aqueous solubility and short in vivo half-life limit direct clinical use. Its derivative Yoda2, together with the structurally distinct Jedi1 and Jedi2, shows improved pharmacological properties and provides diversified tools for evaluating whether moderate PIEZO1 activation can promote intestinal barrier repair[44].

PIEZO1 inhibitors fall into non-competitive and competitive classes. Non-competitive inhibitors include pore blockers such as ruthenium red and gadolinium, and membrane lipid bilayer modulators such as grammostola mechanotoxin 4 (GsMTx4) and Aβ peptides. Competitive inhibitors such as Dooku1 antagonize the Yoda1 binding site. Among them, GsMTx4 is a peptide PIEZO1 inhibitor derived from the venom of the Chilean rose tarantula. It inhibits mechanosensitive channels by altering membrane-tension transmission rather than by directly blocking the pore[45]. Dooku1 acts as a reversible antagonist of Yoda1 and is mainly used to validate PIEZO1-dependent mechanisms. Studies have confirmed that the PIEZO1 inhibitors described above share a common mechanism of reducing Ca²⁺ influx and can exert protective effects in animal models of intestinal barrier injury[46–48]. Additionally, the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) (IC₅₀ about 300 nmol/L) exerts a tonic inhibitory effect on endothelial PIEZO1 channels, exogenous PIP2 supplementation corrects gain-of-function PIEZO1 channelopathies across multiple disease models and restores impaired functional hyperemia in vivo[49].

It has been reported that several compounds derived from traditional Chinese medicine (TCM) can regulate PIEZO1 activity. Among them, Tubeimoside I is the natural PIEZO1 inhibitor with relatively well-established evidence to date, and it shows antiproliferative activity in various GI cancers[50]. Salvianolic acid B, a representative blood-activating and stasis-resolving constituent, may be involved in regulating mechanical-force signaling during intestinal ischemia–reperfusion injury[51]. ChangYong ecoction (CYD), a classical TCM formula, exerts anti‑colorectal cancer effects by downregulating PIEZO1 expression, which in turn inhibits the PI3K/AKT signaling pathway. Consequently, CYD induces ferroptosis and apoptosis while suppressing proliferation and migration[52].

Despite well-defined targets, most PIEZO1 modulators remain research probes rather than clinical agents[53]. It should be noted that only a few of these monomeric compounds have been directly validated by electrophysiology or gene-knockout experiments, while most are supported only by indirect evidence. Robust data enabling their translation into clinical agents capable of restoring intestinal homeostasis are still lacking, highlighting an urgent need for further translational research, ideally combined with molecular docking and cryo-EM structural analysis to confirm their interactions with PIEZO1.

Conclusion

PIEZO1 is an important mechanosensitive ion channel with a highly plastic structure that allows it to effectively transduce mechanical forces into electrical signals. PIEZO1 mediates calcium ion influx in the intestine by sensing mechanical stimuli such as stretching, activating downstream signalling pathways, and regulating intestinal peristalsis, inflammatory response, apoptosis, tissue repair, and metabolic processes. Research has systematically elucidated the multi-level mechanisms of action from molecular structure to cellular function to organ physiology, providing new insights into intestinal mechanosensing and related diseases while laying a theoretical foundation for developing therapeutic strategies targeting PIEZO1.

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The Author(s) 2026. This article is published by Higher Education Press at journal.hep.com.cn.