Xinghuang Liu, Ruohang He, Zhiyue Xu, Xiaochuan Dong, Dongke Wang, Jie Chen, Biqiang Zhu, Jun Song, Xiaohua Hou, Tao Bai
Piezo1 plays a critical role in the sensing of pathological extracellular matrix stiffness in intestinal fibrosis, driving an ROS-EMT axis that promotes disease progression. Targeting Piezo1 or its downstream ROS pathway, for instance with vitamin C, represents a potential therapeutic strategy for intestinal fibrosis.
BACKGROUND AND AIMS: Intestinal fibrosis involves extracellular matrix stiffening. Piezo1, a mechanosensitive ion channel highly expressed in intestinal epithelial cells (IECs), may sense this change. We investigated whether IEC Piezo1 drives fibrosis and explored the underlying mechanobiological mechanism.
METHODS: Dextran sulfate sodium (DSS)-induced fibrosis models, inflammatory bowel disease (IBD) patient samples, and IEC-specific Piezo1 knockout (Piezo1ΔIEC) mice were used. RNA-sequencing, Seahorse assays, and stiffness-gradient hydrogels (1-10 kPa) were applied to assess Piezo1 function, oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS), epithelial-mesenchymal transition (EMT) of IECs, and the anti-fibrosis effect of vitamin C.
RESULTS: Piezo1 expression was significantly upregulated in IECs from fibrotic regions of both DSS model mice and IBD patients. IEC Piezo1 deficiency alleviated DSS-induced intestinal fibrosis without substantially altering chronic inflammation or fibroblast activation/proliferation. Piezo1 deficiency suppressed the partial EMT phenotype in IECs, as evidenced by preserved E-cadherin and Claudin-1 expression. RNA-sequencing and functional assays revealed enhanced OXPHOS activity in Piezo1-deficient IECs. In vitro, matrix stiffness of 4 kPa (mimicking fibrotic tissue) activated Piezo1, increased intracellular Ca2+ and ROS accumulation, and induced EMT. Knockout of Piezo1 or treatment with vitamin C prevented these stiffness-induced changes. Oral administration of high-dose vitamin C in vivo reduced intestinal fibrosis and suppressed IEC EMT.
CONCLUSIONS: Piezo1 plays a critical role in the sensing of pathological extracellular matrix stiffness in intestinal fibrosis, driving an ROS-EMT axis that promotes disease progression. Targeting Piezo1 or its downstream ROS pathway, for instance with vitamin C, represents a potential therapeutic strategy for intestinal fibrosis.