Exploring the mechanism of dihydromyricetin in alleviating psoriasis based on metabolomics, network pharmacology and experimental validation.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Dihydromyricetin (DHM) is a natural product isolated from Nekemias grossedentata (Hand.-Mazz.) J. Wen & Z. L. Nie. It is a long-established ethnic tea medicine, which is widely used in the treatment of itching, dermatitis, psoriasis (PsO) and other skin disorders. However, the mechanism of action of DHM in the treatment of PsO remains to be investigated. AIM OF THE STUDY: To determine the effect of DHM on PsO-related pathological indicators and elucidate its underlying mechanisms of action. MATERIALS AND METHODS: In this study, the PsO mouse model was established using imiquimod (IMQ) induction to evaluate the therapeutic effect of DHM. Assessments included psoriasis area and severity index (PASI) scoring, histopathological and inflammatory cytokine levels measured by ELISA. In TNF-α-stimulated HaCaT cells, the effect of DHM on proliferation was evaluated using an EdU assay. Network pharmacology and molecular docking were applied to screen and validate potential targets of DHM for PsO treatment, followed by Western blot (WB) to elucidate the underlying mechanisms. Untargeted metabolomics identified indoleacetic acid (IAA) as a key metabolite, whose efficacy was further confirmed in vivo. RESULTS: DHM significantly ameliorated IMQ-induced pathological indicators in PsO mice. The results showed that DHM enhanced the activity of antioxidant markers T-AOC and CAT, reduced MDA content, downregulated the expression of Ki67, IL-17, and IL-23 in mouse skin tissue. Furthermore, DHM effectively inhibited TNF-α-induced hyperproliferation of HaCaT cells. Network pharmacology screened four key targets of DHM, and molecular docking showed that DHM docked well with the targets. And the Western blot experiment confirmed that DHM inhibited the PI3K/AKT1/mTOR pathway. Untargeted metabolomics revealed that DHM promoted the production of IAA, which was further validated to alleviate epidermal thickening, mitigate inflammatory responses, and reduce PASI scores in PsO mice. CONCLUSION: DHM alleviates PsO related pathology by inhibiting the PI3K/AKT1/mTOR pathway. This therapeutic effect is partially mediated through the promotion of IAA production, which subsequently reduces epidermal thickening and ameliorates symptoms.