A novel biomimetic nanozyme orchestrates ulcerative colitis resolution by targeting KEAP1-NRF2-ARE pathway: Redox balance restoration, colonic barrier repair, immune homeostasis regulation

Ulcerative colitis (UC) leads to systemic complications with excessive oxidative stress, colonic barrier damage, and inflammation. Deuterohemin-AlaHisThrValGluLys (DhHP-6) is the biomimetic nanozyme rationally designed to mimic the peroxidase activity of Microperoxidase-11. It exhibits potent antioxidant properties, which might emerge as a promising therapeutic candidate compound for UC. In this paper, we aimed to probe the therapeutic effects of DhHP-6 on UC and clarify the underlying molecular mechanisms. We employed dextran sulfate sodium-induced C57BL/6 J male mice for <i>in vivo</i> studies. Lipopolysaccharides-induced intestinal epithelial (Caco-2) and macrophage (RAW264.7) cells were established for <i>in vitro</i> studies. Immunofluorescence, reactive oxygen species (ROS) assays were utilized to evaluate the therapeutic effects on UC. Mitochondrial function assessment, Western blotting analysis, luciferase reporter assays, and AlphaFold 3 studies, the mechanism by which DhHP-6 affected UC via NRF2 was explored. DhHP-6 ameliorated UC by eliminating ROS to protect the colonic barrier and immune homeostasis. It upregulated NRF2 expression, validated by the enhanced NRF2/ARE luciferase activity (<i>p</i> < 0.001) and NRF2 immunofluorescence. AlphaFold 3 analysis revealed the stable binding of DhHP-6 to the KEAP1 Kelch domain, which might interfere with the KEAP1-NRF2 interaction. The activation of NRF2 restored mitochondrial function, inhibited apoptosis, and attenuated inflammation. In summary, DhHP-6 exerted multi-dimensional therapeutic effects on UC, which were underpinned by the activation of the KEAP1-NRF2-ARE pathway as demonstrated through <i>in vivo</i>, <i>in vitro</i>, and <i>in silico</i> analyses. Therefore, DhHP-6 might be a highly promising candidate compound for the management of UC.