Pirfenidone and nintedanib are only anti-pulmonary fibrosis (PF) drugs approved by the FDA. However, they are not target specific, and unable to modify the disease status. Therefore, it is still desirable to discover more effective agents against PF. Vimentin (VIM) plays key roles in tissue regeneration and wound healing, but its molecular mechanism remains unknown. In this work, we demonstrated that atractylodinol (ATD) significantly inhibits TGF-β1-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transition in vitro. ATD also reduces bleomycin-induced lung injury and fibrosis in mice models. Mechanistically, ATD inhibited TGF-β receptor I recycling by binding to VIM (KD = 454 nM) and inducing the formation of filamentous aggregates. In conclusion, we proved that ATD (derived from Atractylodes lancea) modified PF by targeting VIM and inhibiting the TGF-β/Smad signaling pathway. Therefore, VIM is a druggable target and ATD is a proper drug candidate against PF. We prove a novel VIM function that TGF-β receptor I recycling. These findings paved the way to develop new targeted therapeutics against PF.
Keywords: TGF-β receptor; TGF-β/Smad; atractylodinol; pulmonary fibrosis; vimentin.
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