Baicalein disrupts the KEAP1-NRF2 interaction to alleviate oxidative stress injury by inhibiting M1 macrophage polarization.

Macrophages are key players in maintaining the balance of tissues and dealing with inflammation, carrying out vital functions specific to different tissues while safeguarding the body against infections. The intricate interplay between oxidative stress and macrophage polarization and how this contributes to pneumonia is not fully understood. Herein, a predominant accumulation of baicalein in lung macrophages of pathogen-infected mice was observed by an alkynyl-modified probe. Baicalein effectively reduces oxidative stress in vivo and in vitro by modulating the KEAP1-NRF2/ARE signaling pathway. Further investigation indicated that baicalein has inhibitory effects on M1 macrophage polarization and phagocytic capacity, reducing inflammatory cytokine expression. As a protein-protein interaction (PPI) inhibitor, baicalein disrupts the KEAP1-NRF2 interaction by competitively binding to the DGR/Kelch domain of KEAP1. This process helps NRF2 move to the nucleus, which activates the antioxidant transcriptional program, suppresses the production of reactive oxygen species (ROS), and mitigates oxidative stress damage. These findings suggest a different approach to developing treatments for oxidative stress that focuses on inhibiting the interaction between KEAP1-NRF2.