Topical administration of coumarin derivatives alleviates skin inflammatory symptoms in atopic dermatitis model

The prevalence of atopic dermatitis (AD), a chronic inflammatory skin condition, is increasing. Coumarin derivatives, plant secondary metabolites, possess anti-inflammatory properties, but their specific role in AD treatment remain unclear. This study investigated the therapeutic potential of 7-geranyloxycoumarin (C#6), a selective coumarin derivative, in alleviating AD-like symptoms through multifaceted mechanisms. Among various coumarin derivatives tested, C#6 demonstrated remarkable efficacy in both in vitro and in vivo models. Notably, C#6 significantly suppressed interleukin-8 and thymic stromal lymphopoietin production in stimulated HaCaT cells. Experiments on an MC903-induced mouse model of AD revealed that topical administration of C#6 for 10 days led to a significant reduction in ear and epidermal thickness. Flow cytometry analysis showed a significant decrease in CD45 + leukocytes, eosinophils, and Th2 cells in C#6-treated AD mice. Importantly, 16S rRNA sequencing indicated that C#6 restored the disrupted skin microbiome by increasing the abundance of beneficial Lactobacillus and reducing pathogenic bacteria such as Enterobacteriaceae, Corynebacteriaceae, and Corynebacterium, contributing to maintaining skin microbiome balance. Molecular docking studies revealed high binding affinities of C#6 to key regulators, including NOD1, TLR2, PAR2, and TLR3, suggesting a role in modulating critical inflammatory pathways. Additionally, co-culture experiments revealed that C#6 treatment of TNF-α and IFN-γ-stimulated HaCaT cells suppressed inflammatory cytokines expression by THP-1 cells. Collectively, these findings demonstrate that C#6 exerts its anti-atopic effects by suppressing Th2-driven inflammation, reducing eosinophilic infiltration, modulating immune-epidermal crosstalk, and maintaining skin microbiome homeostasis, highlighting its potential as a promising therapeutic agent for AD management.