Platycodin D2 Targets Vimentin to Suppress Fibroblast-Myofibroblast Transition: A Novel Therapeutic Strategy Against Pulmonary Fibrosis
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Background
Pulmonary fibrosis is a progressive lung disease characterized by excessive extracellu-lar matrix deposition and irreversible decline in lung function with limited effective therapeutic targets. Vimentin, a type III intermediate filament protein, plays a critical role in fibroblast activation and fibrogenesis, representing a promising drug target.
Methods
Novel vimentin ligands were screened via virtual screening. SPR assay verified compound-vimentin binding affinity. CETSA and CD spectroscopy analyzed protein structural changes after compound binding. In vitro FMT model and in vivo bleomycin-induced pulmonary fibrosis model were used to assess antifibrotic effects, and mutagenesis assays identified key binding amino acid residues.
Results
Platycodin D2 (PD2) from Platycodon grandiflorus was identified as a novel high-affinity vimentin ligand (Kd = 392.8 nM). PD2 binds vimentin directly, alters its secondary structure and induces insoluble aggregation. It effectively inhibits TGF-β1-induced FMT in vitro and mitigates bleomycin-induced pulmonary fibrosis in vivo, reducing collagen deposition and improving animal survival. Critically, mutagenesis val-idation confirmed that key residues (Glu138 in chain A, Glu132 and Glu143 in chain B, as well as Glu50 and Arg54 in chain C) are essential for this interaction.
Conclusions
Our findings establish PD2 as a novel pharmacological inducer of aberrant vimentin aggregation, presenting a distinct target-driven strategy for antifibrotic drug development.
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Platycodin D2 Targets Vimentin to Suppress Fibroblast-Myofibroblast Transition: A Novel Therapeutic Strategy Against Pulmonary Fibrosis https://www.biorxiv.org/content/10.64898/2026.11.03.763586v1
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Platycodin D2 Targets Vimentin to Suppress Fibroblast-Myofibroblast Transition: A Novel Therapeutic Strategy Against Pulmonary Fibrosis https://www.biorxiv.org/content/10.64898/2026.11.03.763586v1
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