Integrated serum metabolomics and network pharmacology approach to reveal the potential mechanisms of withanolides from the leaves of Datura metel L. on psoriasis.

• An integrated strategy of metabolomics coupled with network pharmacology was adopted to provide a global view of the efficacy of withanolides for psoriasis treatment. • The network about "metabolites-pathways-targets-active components" was constructed by combining the metabolomics and network pharmacology. • Two types of pathways, angiogenesis and inflammation, including sphingolipids metabolism and HIF-1α/ VEGF pathway were involved in the action mechanisms of withanolides for treating psoriasis. Psoriasis is a chronic, immune-mediated inflammatory skin disease and highly depends on inflammation and angiogenesis as well as other pathways. Our previous study showed that the withanolides from the leaves of Datura metel L. exhibited significant therapeutically effect on psoriasis, but the mechanisms concerning this effect have not been systematically studied. The purpose of this paper was to investigate the possible mechanism of withanolides for treating psoriasis using an integrated metabolomics and network pharmacology strategy. Untargeted metabolomics profiling of serum with UHPLC/Orbitrap MS and a multivariate data method were performed to discover the potential biomarkers and metabolic pathways. Afterward, the compound-target-pathway network of withanolides for psoriasis was constructed by virtue of network pharmacology. Finally, the crucial pathways were selected by integrating the results of metabolomics and network pharmacology, and then validated by ELISA and western blot analysis. The results showed that withanolides could exert excellent effects on psoriasis through regulating two types of pathways, angiogenesis and inflammation, including sphingolipids metabolism and HIF-1α/VEGF pathway, reflected by inhibiting the production of inflammatory cytokines (IL-1β, IL-6, IL-8, IFN-γ, TNF-α, HIF-1α and VEGF), as well as reducing the protein expressions of HIF-1α and VEGF. Our study successfully explained the polypharmcological mechanisms underlying the efficiency of withanolides from the D. metel L. leaves on treating psoriasis. Meanwhile, it was also valuable for performing a systematical investigation of herb medicines, as well as for efficiently predicting the therapeutic mechanisms of traditional Chinese medicine. [ABSTRACT FROM AUTHOR]