Dextran sodium sulfate (DSS)-induced colitis is alleviated in mice after administration of flavone-derived NRF2-activating molecules

Abstract

Inflammatory Bowel Disease (IBD) is a chronic and relapsing inflammatory condition characterized by severe symptoms such as diarrhea, fatigue, and weight loss. Growing evidence underscores the direct involvement of the nuclear factor-erythroid 2-related factor 2 (NRF2) in the development and progression of IBD, along with its associated complications, including colorectal cancer. The NRF2 pathway plays a crucial role in cellular responses to oxidative stress, and dysregulation of this pathway has been implicated in IBD. Flavones, a significant subclass of flavonoids, have shown pharmacological impacts in various diseases including IBD, through the NRF2 signaling pathway. In this study, we conducted a screening of compounds with a flavone structure and identified NJK15003 as a promising NRF2 activator. NJK15003 demonstrated potent NRF2 activation, as evidenced by the upregulation of downstream proteins, promoter activation, and NRF2 nuclear translocation in IBD cellular models. Treatment with NJK15003 effectively restored the protein levels of tight junctions in cells treated with dextran sodium sulfate (DSS) and in DSS-treated mice, suggesting its potential to protect cells from barrier integrity disruption in IBD. In DSS-treated mice, the administration of NJK15003 resulted in the prevention of body weight loss, a reduction in colon length shortening, and a decrease in the disease activity index. Furthermore, NJK15003 treatment substantially alleviated inflammatory responses and apoptotic cell death in the colon of DSS-treated mice. Taken together, this study proposes the potential utility of NRF2-activating flavone compounds, exemplified by NJK15003, for the treatment of IBD.