Studies on the regulation of mucin2 expression in intestinal goblet cells by the endocrine system and the immune system have been comprehensive, but the effects of abundant mechanical factors in the intestinal microenvironment on goblet cells are not clear.

We constructed mechanical stimulation models in vivo and in vitro to explore the effect of mechanical stimulation on intestinal goblet cells. Piezo1 expression and function were regulated through model mouse and drugs to explored whether Piezo1 mediated mechanical stimulation.

The results showed that hydrostatic pressure could promote mucus secretion in the mouse colon, and both traction force and shear force could promote the expression of mucin2 in the LS174T cell line. We further found that the Piezo1 protein, which was abundantly expressed in goblet cells, acted as a mechanoreceptor. Knockout of Piezo1 in the intestinal epithelial cells of mice could reduce the promotion of mucus secretion by pressure stimulation, and the specific downregulation of Piezo1 protein in LS174T cells or Piezo1 inhibitor treatment could significantly reduce the promotion of mucin2 expression in goblet cells by mechanical stimulation; however, treatment with a Piezo1 agonist had the opposite effect. Moreover, we found that Piezo1 regulated mucin2 expression through the downstream Erk/Ca²⁺ pathway.

In short, our study confirmed for the first time that goblet cells are mechanoreceptive cells that can directly sense mechanical stimulation in the intestinal tract and respond back through the Piezo1‐Erk/Ca²⁺‐mucin2 pathway.