Accordantly with the results obtained in vivo, we found that DSC inhibited Nox4 expression and subsequent mitochondrial ROS and intracellular H2O2 generation in vitro. Similarly, Nox4 knockdown also decreased LPS‐induced mitochondrial ROS and intracellular H2O2 production in BMDM. Meanwhile, our data demonstrated that genetic Nox4 knockdown also significantly attenuated colonic injury in DSS‐induced colitis. This evidence concerns the gene NOX4 and colitis.