Formononetin ameliorates bleomycin-induced pulmonary fibrosis in mice via targeting USP5.

Authors

Yongping Wang, Xueze Liu, Hao Song, Cheng Yang

Published in

Journal of thoracic disease. Volume 18. Issue 8. Pages 839. Aug 31, 2026. Epub Aug 28, 2026.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with limited therapeutic options. Transforming growth factor beta 1 (TGF-β1) is a major profibrotic mediator that promotes fibroblast activation and extracellular matrix (ECM) deposition. This study aimed to evaluate the therapeutic effects of formononetin on bleomycin-induced pulmonary fibrosis (PF) and investigate its underlying mechanism and potential molecular target.
A TGF-β1-responsive luciferase reporter system was used to screen natural compounds that inhibit TGF-β signaling. The effects of formononetin on cell viability, fibroblast activation, and the expression of α-smooth muscle actin (α-SMA), collagen I (Col-1), and fibronectin (Fn) were examined in vitro. Its therapeutic effects were further evaluated in a bleomycin-induced PF model in male C57BL/6 mice. Lung function, histopathological changes, collagen deposition, and inflammatory cells and mediators in bronchoalveolar lavage fluid (BALF) were assessed. Molecular docking and small interfering RNA experiments were performed to investigate ubiquitin-specific peptidase 5 (USP5) as a potential target.
Formononetin inhibited TGF-β1-induced reporter activity and significantly reduced the messenger RNA and protein levels of α-SMA, Col-1, and Fn in fibroblasts. In bleomycin-treated mice, formononetin improved lung function, attenuated histopathological fibrosis and collagen deposition, and reduced pulmonary inflammation. Mechanistically, the findings indicated that formononetin inhibited USP5, increased p53 transcription and expression, and subsequently suppressed TGF-β1/Smad signaling and fibroblast activation.
Formononetin attenuated bleomycin-induced PF in mice, potentially through the USP5/p53/TGF-β1/Smad signaling axis. These findings support further investigation of formononetin as a potential candidate for PF treatment.

PMID:
42724742
Bibliographic data and abstract were imported from PubMed on 11 Sep 2026.

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