Tyrosine kinase 2 inhibition by GL‐V9 treats psoriasiform dermatitis via macrophage‐helper T‐cell modulation

BACKGROUND AND PURPOSE: Psoriasis (PsO) is a chronic T lymphocyte-mediated inflammatory disease arising on a polygenic background. GL-V9, a structurally optimized flavonoid with reported anti-inflammatory and anti-fibrotic activities, was investigated as a potential therapeutic agent for PsO. EXPERIMENTAL APPROACH: The therapeutic and relapse-preventive effects of GL-V9 were evaluated in multiple murine models of psoriasiform inflammation. To define its immunomodulatory actions, we established distinct immune-cell polarization models, including macrophage and T helper cell models, and assessed inflammatory mediator production, immune-cell polarization and intercellular communication within psoriatic lesions. Mechanistic studies further examined the interaction between GL-V9 and tyrosine kinase 2 (TYK2), and the functional relevance of TYK2 using siTYK2-mediated knockdown in bone marrow-derived macrophages and THP-1 cells. KEY RESULTS: GL-V9 effectively alleviated established psoriasiform dermatitis and reduced disease relapse. Mechanistically, preliminary evidence indicated that GL-V9 binds to the pseudokinase domain of TYK2 and suppresses JAK/STAT activation, thereby reducing the production of pro-inflammatory cytokines and chemokines. In M1 macrophages and T helper 1 (Th1) cells, GL-V9 disrupted TYK2-dependent signalling, altered pathogenic polarization states and weakened inflammatory communication with neighbouring immune cells, collectively restoring a more balanced immune microenvironment. CONCLUSIONS AND IMPLICATIONS: GL-V9 ameliorates PsO by targeting TYK2-STAT signalling and reshaping macrophage-T helper cell-driven inflammation. These findings support GL-V9 as a promising therapeutic candidate for PsO and other TYK2-mediated inflammatory diseases.