Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease affecting the gastrointestinal tract. Although paeonol has been used for treating UC due to its anti-inflammatory and antioxidant effects, the underlying mechanisms remain unclear. In this study, we investigated the mechanisms of paeonol's action on UC by conducting in-vitro and in-vivo studies using NCM460 cells and RAW264.7 cells, and the DSS-induced mice colitis model. The in vitro studies demonstrate that paeonol exerts inhibitory effects on the activation of the NF-κB signaling pathway through upregulating PPARγ expression, thereby attenuating pro-inflammatory cytokine production, reducing reactive oxygen species levels, and promoting M2 macrophage polarization. These effects are significantly abrogated upon addition of the PPARγ inhibitor GW9662. Moreover, UC mice treated with paeonol showed increased PPARγ expression, which reduced inflammation and apoptosis to maintain intestinal epithelial barrier integrity. In conclusion, our findings suggest that paeonol inhibits the NF-κB signaling pathway by activating PPARγ, reducing inflammation and oxidative stress and improving Dss-induced colitis. This study provides a new insight into the mechanism of treating UC by paeonol.Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by inflammation and ulcers in the innermost aspect of the colon and rectum of unknown etiology. Given the high incidence of UC in developed countries and the significant increase in developing countries, it has developed into a global burden 1 . In addition, cases have been reported at all ages, from children to the elderly 2 . UC is also known to increase the risk of colorectal cancer (CRC) 3 . Multiple factors, including environmental factors, genetic polymorphism, and mucosal immune dysregulation, have been thought to play important roles in the pathogenesis of UC. Although the etiology of UC remains unclear, accumulating evidence suggests that the increased secretion of pro-inflammatory cytokines and dysregulation of the intestinal immune system play an important role in the disruption of the gastrointestinal mucosal barrier and the persistence of inflammation 4 . Studies have revealed that a large number of activated macrophages can secrete inflammatory cytokines in the colonic mucosa of patients with UC 5 . The levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in the sera and colonic tissues of patients with UC were significantly higher than those of normal subjects, and their downregulation could alleviate UC 6 . As the central component of the cellular signaling machinery, nuclear factor-kB (NF-κB) regulates immune response and inflammation, and it is closely related to the occurrence and development of UC 7,8 . Many of the aforementioned inflammatory factors are highly dependent on NF-κB-associated signal transduction. NF-κB, which is expressed in almost all cell types, can be activated by a vast range of stimuli, including microbial components, chemokines, reactive...
