Platycodin D2 Targets Vimentin to Suppress Fibroblast-Myofibroblast Transition: A Novel Therapeutic Strategy Against Pulmonary Fibrosis

Pulmonary fibrosis, a debilitating lung disorder marked by excessive extracellular matrix accumulation and irreversible lung function decline, presents few therapeutic options. Fibroblast activation and fibrogenesis hinge on vimentin, a type III intermediate filament protein, offering a potential drug target. Researchers screened for vimentin ligands using virtual screening.

Subsequent SPR assays confirmed the compound-binding affinity to vimentin. CETSA and CD spectroscopy were then employed to monitor structural alterations in proteins post-binding. In vitro FMT and in vivo bleomycin-induced pulmonary fibrosis models were utilized to evaluate antifibrotic efficacy. Mutagenesis assays were conducted to pinpoint pivotal binding amino acid residues.

Platycodin D2 (PD2), extracted from Platycodon grandiflorus, emerged as a promising novel high-affinity vimentin ligand with a dissociation constant of 392.8 nM. PD2 directly binds vimentin, modifies its secondary structure, and triggers insoluble aggregation. Its capacity to inhibit TGF-{beta}1-induced FMT in vitro and alleviate bleomycin-induced pulmonary fibrosis in vivo is noteworthy.

Moreover, mutagenesis validation validated that crucial residues (Glu138 in chain A, Glu132 and Glu143 in chain B, along with Glu50 and Arg54 in chain C) are imperative for this interaction. In summary, PD2 has been identified as a groundbreaking pharmacological agent that induces aberrant vimentin aggregation, providing a unique target-driven approach for the development of antifibrotic drugs.