Intestinal epithelial PIEZO1 regulates macrophage-to-myofibroblast transition via epithelial-derived TGF-α signaling in Crohn’s disease

Intestinal fibrosis represents a common complication of Crohn’s disease (CD). Previous studies have shown that PIEZO1 is enriched in the colonic mucosal epithelial cells of patients with CD. However, whether epithelial PIEZO1 contributes to intestinal fibrosis in CD remains unclear. The present study investigated whether PIEZO1 in intestinal epithelial cells (IECs) regulates intestinal fibrosis by modulating macrophage-to-myofibroblast transition (MMT). Western blotting, real-time PCR, Masson’s trichrome staining and immunofluorescence were used to evaluate the association between PIEZO1 and MMT in vivo and in vitro. Conditioned medium (CM) derived from IECs was used to assess its effects on macrophage phenotype. Co-immunoprecipitation, single-cell RNA sequencing and Enzyme-linked immunosorbent assay were performed to identify the mechanism through which PIEZO1 signaling in IECs regulates MMT. Intestinal fibrosis in patients with CD was positively correlated with the MMT process. CM derived from IECs with elevated PIEZO1 activity promoted MMT. Mechanistically, elevated PIEZO1 activity in IECs was associated with increased TGF-α secretion, which was accompanied by activation of the PKA/NF-κB P65 signaling pathway in macrophages. Furthermore, in a chronic DSS-induced colitis–associated fibrosis model, IEC-specific PIEZO1 deficiency attenuated intestinal fibrosis. These findings suggest that epithelial PIEZO1 regulates MMT and intestinal fibrosis in CD, potentially involving TGF-α–mediated signaling.