The mechanosensitive ion channel Piezo1 promotes colitis by modulating oxidative stress and ferroptosis-related markers.

Piezo1 plays a crucial role in the gastrointestinal tract. However, whether Piezo1 induces intestinal dysfunction and mitochondrial damage in dextran sulfate sodium (DSS)-induced colitis, and the underlying mechanisms involved, remains unclear. We aimed to investigate whether Piezo1 triggers oxidative stress, alters ferroptosis-associated markers, and induces intestinal epithelial injury in human intestinal epithelial cells (HIECs) and in the colonic tissues of mice with DSS-induced colitis. We established a DSS-induced colitis mouse model by administering 1.5% DSS in drinking water and performed Piezo1-related mechanical stimulation experiments in HIEC-6 cells. Western blotting and immunofluorescence were employed to explore the mechanism by which Piezo1 affects oxidative stress and ferroptosis-related markers in intestinal epithelial cells. Our results revealed significant inflammation and oxidative stress responses in intestinal epithelial cells. The Piezo1 agonist activated inflammatory and oxidative stress responses in intestinal epithelial cells, while the Piezo1 inhibitor GsMTx4 significantly reversed these responses. We also observed increased expression levels of NADPH oxidase (NOX), NOX4, and reactive oxygen species (ROS). Piezo1 activation increased protein kinase C expression, NOX activity, and ROS levels. Piezo1 was significantly upregulated in the colonic tissues of DSS-induced colitis mice and was associated with oxidative stress and inflammation. The Piezo1 inhibitor markedly attenuated ferroptosis-associated changes by reducing tissue ROS, malondialdehyde, Fe2+, and acyl-CoA synthetase long-chain family member 4 levels, while increasing glutathione, ferritin heavy chain 1, and glutathione peroxidase 4 levels. Our results indicate that Piezo1 may exacerbate DSS-induced colitis by promoting oxidative stress and modulating ferroptosis-associated markers in colonic tissue.