Piezo1 in digestive homeostasis and disease: Barrier function, immune signalling, cellular injury and metabolism.

BACKGROUND: Piezo1 is a mechanosensitive cation channel that converts stretch, compression, and shear stress into calcium-dependent signals. This narrative review evaluates how Piezo1 contributes to digestive physiology and disease and why divergent outcomes arise across experimental contexts. MAIN BODY: We searched PubMed/MEDLINE, Embase, Web of Science, and Scopus from database inception to 15 July 2026, prioritising primary studies that used Piezo1-specific genetic or pharmacological interventions. Piezo1-specific evidence supports roles in epithelial junctional adaptation, mucus production, stem-cell renewal, immune activation, injury, fibrosis, and gastrointestinal endocrine signalling. A contextual framework based on cell identity and state, mechanical stimulus, and tissue or disease phase helps explain these divergent effects. Transient physiological activation may support homeostasis and repair, whereas persistent or excessive activation can promote Ca2+ overload, inflammasome signalling, mitochondrial dysfunction, and matrix remodelling. The strongest digestive-system evidence for mechanometabolic coupling concerns macrophage glycolysis, enterocyte nutrient handling, and selected endocrine and lipid-regulatory pathways. Evidence for Piezo1-dependent lactate production remains model-specific, and direct digestive evidence for lactylation is absent. One mechanistic mouse study supports hepatic endothelial regulation of bile-acid synthesis, whereas intestinal Piezo1 control of bile-acid homeostasis remains unestablished. CONCLUSION: Therapeutic translation is limited by non-selective tool compounds, broad tissue expression and the need for targeted delivery and phase-appropriate modulation. Piezo1 is therefore best viewed as a context-dependent mechanotransducer rather than a uniformly pathogenic target.