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

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.

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.

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.

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.