Furin inhibits epithelial cell injury and alleviates experimental colitis by activating the Nrf2-Gpx4 signaling pathway

Furin is a proprotein convertase reported to have protective effects in several autoimmune diseases. However, the role of furin in ulcerative colitis (UC) remains unclear. We aimed to clarify this role.Furin expression was measured in UC and dextran sulfate sodium (DSS)-induced colitis. Gain- and loss-of-function experiments were conducted to evaluate the effect of furin in UC using DSS-treated NCM460 cells. Several ferroptotic parameters, including cell viability, cell death rate, lipid reactive oxygen species level, mitochondrial membrane damage and glutathione peroxidase 4 (Gpx4) expression, were measured. Exogenous furin was used to treat the DSS-induced colitis in mice to confirm the results in vivo. Finally, the activation of nuclear factor erythroid 2-like 2 (Nrf2) was detected to explore the mechanism.Furin expression was aberrant in UC. Furin overexpression attenuated DSS-induced ferroptosis-like injury and upregulated Gpx4 in NCM460 cells, whereas silencing furin had the opposite effects. Exogenous furin treatment alleviated DSS-induced colitis in mice by upregulating Gpx4. Mechanistic experiments revealed that furin activated Nrf2 both in vitro and in vivo.Furin protects epithelial cells from DSS-induced ferroptosis-like cell injury and alleviates experimental colitis by activating the Nrf2-Gpx4 signaling pathway.