Oroxylin A attenuates psoriasiform skin inflammation by direct targeting p62 (sequestosome 1) via suppressing M1 macrophage polarization

Background and Purpose Psoriasis results from the interplay of innate and adaptive immunity in the skin. Oroxylin A (OA) has shown anti‐inflammatory effects in various disorders. This study explores oroxylin A potential in treating psoriasis, particularly its impact on type I macrophage (Mφ1) polarization. Experimental Approach Oroxylin A‐mediated therapeutic effects were evaluated using imiquimod‐induced or IL‐23‐injected psoriatic mice models, followed by proteomics assays to predict potential signalling and targeting proteins. Immunofluorescence and immunoblot assays verified that oroxylin A suppresses NF‐κB signalling in Mφ1 macrophages. Co‐immunoprecipitation and microscale thermophoresis (MST) assays further demonstrated that p62 (sequestosome 1) is the target protein for oroxylin A in macrophages. Oroxylin A‐p62‐mediated suppression of psoriasis was validated in an imiquimod‐induced p62 conditional knockout (cKO) mice model. Key Results Oroxylin A demonstrated therapeutic efficacy in murine models induced by imiquimod or IL‐23 by attenuating cutaneous inflammation and mitigating Mφ1 polarization via NF‐κB signalling. Proteomics analysis suggested SQSTM1/p62 as a key target, confirmed to interact directly with oroxylin A. Oroxylin A disrupted the p62‐PKCζ interaction by binding to PB1 domain of p62. Its anti‐inflammatory effects were significantly reduced in macrophages from p62 cKO mice compared to the wild‐type (WT) mice in psoriasis model, supporting oroxylin A role in suppressing Mφ1 polarization through its interaction with p62. Conclusion and Implications Our findings demonstrated oroxylin A suppressed psoriasiform skin inflammation in mouse models by blocking the PKCζ‐p62 interaction, subsequently inhibiting the activation of NF‐κB p65 phosphorylation in macrophages.