7,8-Dihydroxyflavone alleviates ulcerative colitis by binding keap1 to activate an slc7a11-dependent inhibition of NF-κB p65 signaling in macrophages

Wei Wang; Xiao Wang; Zi-Dan Zhou; Xiao-Bao Deng; Xue-Wei Luo; Qi Wang; Guang-Yu Zhang; Zhe Zhang; Zhong-Sheng Li; Xian-Jin He; Zhen Jin; Chen Yang; Dan Du; You-Zhi Tang

doi:10.1016/j.jare.2026.01.078

7,8-Dihydroxyflavone alleviates ulcerative colitis by binding keap1 to activate an slc7a11-dependent inhibition of NF-κB p65 signaling in macrophages

J Adv Res. 2026 Feb 10:S2090-1232(26)00103-7. doi: 10.1016/j.jare.2026.01.078. Online ahead of print.

Authors

Wei Wang¹, Xiao Wang², Zi-Dan Zhou¹, Xiao-Bao Deng², Xue-Wei Luo², Qi Wang¹, Guang-Yu Zhang³, Zhe Zhang⁴, Zhong-Sheng Li¹, Xian-Jin He¹, Zhen Jin¹, Chen Yang⁵, Dan Du⁶, You-Zhi Tang⁷

Affiliations

¹ Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agriculture University, Guangzhou, Guangdong 510642, China.
² State Key Laboratory of Cellular Stress Biology, Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
³ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
⁴ MOE International Joint Lab for Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
⁵ Department of Stomatology, Siming Branch, Xiang'an Hospital of Xiamen University, Xiamen 361000, China.
⁶ State Key Laboratory of Cellular Stress Biology, Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: dandu@xmu.edu.cn.
⁷ Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agriculture University, Guangzhou, Guangdong 510642, China. Electronic address: youzhitang@scau.edu.cn.

PMID: 41679600
DOI: 10.1016/j.jare.2026.01.078

Abstract

Introduction: Ulcerative colitis (UC) is characterized by episodic occurrences of bloody diarrhea and can lead to potentially fatal complications, highlighting the urgent need for effective and safe therapeutic options.

Objectives: This study aims to conduct a mechanistic investigation into the repurposing of 7,8-Dihydroxyflavone (7,8-DHF), a bioactive flavonoid, for ameliorating the clinical symptoms of dextran sulfate sodium (DSS)-induced ulcerative colitis in mice of both sexes.

Method: To explore the structural-activity relationship of 7,8-DHF, a series of flavone derivatives with different substitution patterns on the A-ring were synthesized. The active 7,8-DHF were evaluated in both LPS-induced RAW 264.7 macrophage and DSS-induced mice UC models. Then we used RNA-sequencing and 16s rRNA sequencing to identify the mechanism underlying of 7,8-DHF and then identified the critical role of slc7a11-mediated macrophage polarization combining with gene silencing and pharmacological intervention. The interaction between slc7a11 and NF-κB p65 in macrophage was verified through immunoprecipitation-mass spectrometry (IP-MS) and Co-Immunoprecipitation (CO-IP). Furthermore, Nrf2/keap1complex dissociation-induced slc7a11 activation was demonstrated using a biotinylated DHF probe in pull-down and molecular dynamic stimulation assays.

Results: Anti-colitis capacity of 7,8-DHF was superior to both 7-hydroxyflavone (7-HF) and 5-aminosalicylic acid (5-ASA) across all measured clinical and histological parameters. The protective effects of 7,8-DHF against DSS-induced colitis are attributed to the binding of its A-ring ortho-dihydroxy moiety to keap1, which leads to the activation of Nrf2 and subsequent upregulation of slc7a11 expression. The increased slc7a11 protein binds to NF-κB p65, sequestering it from the nucleus and thereby reducing NF-κB signaling. This modulation of the NF-κB pathway affects macrophage polarization and gut inflammation. Additionally, treatment with 7,8-DHF specifically increased the abundance of beneficial Akkermansia spp. and decreased pathobionts such as Escherichia-Shigella spp. in the DSS-induced colitis model.

Conclusion: Our study underscores the potential therapeutic application of 7,8-DHF in managing inflammatory conditions, particularly ulcerative colitis.

Keywords: 7,8-dihydroxyflavone; Gut microbiota; Macrophage activation; Slc7a11; Ulcerative colitis.