Myricetin ameliorates bleomycin-induced pulmonary fibrosis in mice by inhibiting TGF-β signaling via targeting HSP90β

Idiopathic pulmonary fibrosis is a progressive-fibrosing lung disease with high mortality and limited therapy, which characterized by myofibroblasts proliferation and extracellular matrix deposition. Myricetin, a natural flavonoid, has been shown to possess a variety of biological characteristics including anti-inflammatory and anti-tumor. In this study we explored the potential effect and mechanisms of myricetin on pulmonary fibrosis in vivo and vitro. The in vivo studies showed that myricetin effectively alleviated bleomycin (BLM)-induced pulmonary fibrosis. KEGG analysis of RNA-seq data indicated that myricetin could regulate the transforming growth factor (TGF)-beta signaling pathway. In vitro studies indicated that myricetin could dose-dependently suppress TGF-beta 1/Smad signaling and attenuate TGF-beta 1-induced fibroblast activation and epithelial-mesenchymal transition (EMT). Molecular docking indicated that heat shock protein (HSP) 90 beta may be a potential target of myricetin, and MST assay demonstrated that the dissociation constant (Kd) of myricetin and HSP90 beta was 331.59 nM. We demonstrated that myricetin interfered with the binding of HSP90 beta and TGF-beta receptor II and impeded fibroblast activation and EMT. In conclusion, myricetin impedes TGF-beta 1-induced lung fibroblast activation and EMT via targeting HSP90 beta and attenuates BLM-induced pulmonary fibrosis in mice.