Mechanosensitive Piezo ion channels, particularly Piezo1 and Piezo2, are gaining recognition as central regulators of digestive system physiology and disease. A comprehensive review highlights how these channels convert mechanical forces such as tissue stretching, fluid flow, and pressure into cellular signals that control gastrointestinal motility, secretion, barrier integrity, immune responses, and cancer progression. The findings position Piezo channels as promising biomarkers and therapeutic targets across a broad range of digestive disorders.
Since their discovery in 2010, Piezo1 and Piezo2 have been identified as critical mechanosensors that respond to physical stimuli by allowing calcium and sodium ions to enter cells. This ion influx triggers signaling pathways that regulate cell behavior, tissue adaptation, and inflammatory responses. Within the digestive tract, Piezo channels help coordinate essential physiological functions, including appetite control, intestinal movement, bile secretion, and interactions between the gut and its microbiota.
The review emphasizes the distinct yet complementary roles of the two channel types. Piezo1 is broadly distributed throughout digestive tissues, including the stomach, liver, pancreas, intestinal epithelium, and enteric nervous system. It regulates processes such as ghrelin secretion, intestinal peristalsis, mucus production, bile flow, and microbial homeostasis. Piezo2, in contrast, is more specialized in sensory pathways, where it mediates mechanosensation, serotonin release, visceral pain perception, and gastrointestinal reflexes.
A key feature of Piezo signaling is its ability to activate major intracellular pathways through calcium influx. As illustrated in the mechanotransduction model presented in the review, Piezo activation stimulates signaling networks including MAPK, RhoA/ROCK, PI3K–Akt, and YAP/TAZ, linking mechanical stress to cellular proliferation, migration, inflammation, and tissue remodeling. These pathways help explain how abnormal mechanical environments can drive disease development.
The review identifies a growing body of evidence linking Piezo dysregulation to several digestive diseases. In hepatocellular carcinoma, elevated Piezo1 expression promotes tumor invasion, angiogenesis, epithelial–mesenchymal transition, and metastasis through pathways involving FAK/Src signaling, TGF-β activation, and HIF-1α stabilization. High Piezo1 expression is associated with more aggressive tumors and poorer clinical outcomes.
In gastric cancer, both Piezo1 and Piezo2 contribute to disease progression. Piezo1 enhances tumor cell proliferation and migration, while Piezo2 expression correlates with advanced disease stage, lymph node metastasis, immune-cell infiltration, and reduced survival. The review highlights the role of the Helicobacter pylori–induced NF-κB–Piezo1–YAP1 signaling axis in remodeling the tumor microenvironment and promoting cancer progression.
Similarly, in colorectal cancer, Piezo1 supports cancer stem-cell maintenance, invasion, and metastasis, whereas Piezo2 promotes lymphangiogenesis and tumor dissemination through the SLIT2/ROBO1/VEGFC pathway. Together, these channels appear to contribute to tumor aggressiveness and resistance to therapy. The schematic overview of digestive system cancers in the review illustrates how Piezo-driven signaling integrates mechanical stress with oncogenic pathways across multiple gastrointestinal malignancies.
Beyond cancer, Piezo channels play important roles in inflammatory and functional gastrointestinal disorders. In inflammatory bowel disease, Piezo1 amplifies inflammation by activating NF-κB and NLRP3 inflammasome pathways, promoting oxidative stress and disrupting intestinal barrier function. Piezo2 contributes to visceral hypersensitivity by enhancing mechanosensory signaling in sensory neurons.
In functional gastrointestinal disorders such as irritable bowel syndrome and functional constipation, Piezo2 drives abnormal pain sensitivity and serotonin-mediated signaling, while Piezo1 affects epithelial permeability and barrier integrity. Experimental evidence suggests that coordinated activity of both channels is essential for normal intestinal motility and sensory regulation.
The review also highlights Piezo1 as a critical mediator of pressure-induced pancreatitis. Mechanical stress activates Piezo1 in pancreatic acinar cells, leading to calcium overload, mitochondrial dysfunction, and premature digestive enzyme activation. Blocking Piezo1 significantly reduces pancreatic injury in experimental models, suggesting a potential preventive strategy for high-risk clinical situations.
Although therapeutic targeting of Piezo channels remains at an early stage, several experimental compounds have shown promise. Piezo1 agonists and inhibitors can modulate inflammation, epithelial repair, and tissue injury in preclinical models. However, because Piezo channels are widely expressed throughout the body, achieving tissue-specific targeting remains a major challenge. Emerging approaches involving organoids, gene-silencing technologies, CRISPR-based interventions, and nanoparticle delivery systems may help overcome these limitations.
As understanding of mechanobiology continues to expand, Piezo ion channels are increasingly viewed as master regulators of digestive system function. Their central role in translating mechanical forces into biological responses offers new opportunities for the diagnosis and treatment of cancers, inflammatory diseases, motility disorders, and other gastrointestinal conditions.
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Reference
Xiangyun Yan, Weijian Zeng, Peitao Ma, Junpeng Yao, Tingting Ma, Ying Li, Piezo ion channels in the digestive system: Mechanotransduction pathways and therapeutic targeting strategies, Genes & Diseases, Volume 13, Issue 5, 2026, 101925, https://doi.org/10.1016/j.gendis.2025.101925

Funding
National Natural Science Foundation of China 82274652