Kaempferol prevents Nrf2 from ubiquitin-mediated proteolysis to mitigate both NLRP3 inflammation and oxidative stress: implications for alleviating DSS-induced colitis in mice

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Abstract
Background Activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and oxidative stress are key pathological hallmarks of inflammatory bowel disease (IBD) and represent novel targets for therapeutic intervention. The therapeutic potential of the naturally occurring flavonoid kaempferol (KAE) in IBD, along with its underlying molecular mechanisms, remains incompletely understood. Methods We established dextran sulfate sodium (DSS)-induced colitis and lipopolysaccharide (LPS)-induced systemic inflammation mouse models. KAE was administered as an intervention. In vitro, peritoneal macrophages (PMs) were stimulated to activate the NLRP3 inflammasome. We comprehensively evaluated the effects of KAE on interleukin-1β (IL-1β) release, NLRP3 inflammasome assembly, and mitochondrial reactive oxygen species (mt-ROS) production. Additionally, we assessed its impact on the Keap1-Nrf2 pathway. Molecular docking and ubiquitin-dependent degradation assays were conducted to confirm Nrf2 as a direct target of KAE. Results KAE significantly attenuated colitis development, marked by reduced NLRP3 expression and enhanced Nrf2 activation. It inhibited both the priming and assembly phases of NLRP3 inflammasome activation. Notably, Nrf2 inhibition completely abolished KAE-mediated removal of mt-ROS and downstream suppression of NLRP3 inflammasome activation. Mechanistically, KAE prevented Nrf2 proteolysis by directly binding to Arg415 of Keap1. Conclusions Our findings demonstrate that KAE acts as an mt-ROS scavenger to protect against inflammatory pyroptosis, offering novel mechanistic insights and a promising therapeutic strategy for colitis treatment.
Funding Information
  • Key Technologies Research and Development Program (2023YFC3502801)
  • National Natural Science Foundation of China (82304755)
  • Medical Science and Technology Project of Zhejiang Province (2024ZL343)

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