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.