Ugonin L ameliorates pulmonary fibrosis as a novel TβRs inhibitor by regulating the TGF-β/TβRs signaling and autophagy

Tzu-Lan Hsia; Wei-Chung Chiou; Hsiu-Chen Huang; Hui-Kang Liu; Jui-Chieh Chen; Pin-Kuei Fu; Cheng Huang

doi:10.1016/j.biopha.2025.118267

Ugonin L ameliorates pulmonary fibrosis as a novel TβRs inhibitor by regulating the TGF-β/TβRs signaling and autophagy

Biomed Pharmacother. 2025 Jun 17:189:118267. doi: 10.1016/j.biopha.2025.118267. Online ahead of print.

Authors

Tzu-Lan Hsia¹, Wei-Chung Chiou², Hsiu-Chen Huang³, Hui-Kang Liu⁴, Jui-Chieh Chen⁵, Pin-Kuei Fu⁶, Cheng Huang⁷

Affiliations

¹ Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei City 112304, Taiwan. Electronic address: karta2969922@gmail.com.
² Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei City 112304, Taiwan. Electronic address: ryanw.chiou@gmail.com.
³ Center for Teacher Education, National Tsing Hua University, Hsinchu City 300044, Taiwan; Department of Applied Science, Nanda Campus, National Tsing Hua University, Hsinchu City 300044, Taiwan. Electronic address: hsiuchen@mx.nthu.edu.tw.
⁴ Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei City 112304, Taiwan; Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei City 110301, Taiwan. Electronic address: hk.liu@nricm.edu.tw.
⁵ Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600355, Taiwan. Electronic address: jcc@mail.ncyu.edu.tw.
⁶ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung City 402010, Taiwan; Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407219, Taiwan; Integrated Care Center of Interstitial Lung Disease, Taichung Veterans General Hospital, Taichung City 407219, Taiwan. Electronic address: yetquen@gmail.com.
⁷ Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei City 112304, Taiwan. Electronic address: chengh@ym.edu.tw.

PMID: 40532575
DOI: 10.1016/j.biopha.2025.118267

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown etiology, affecting about 3 million individuals worldwide. Significant risk factors for IPF include advanced age and infectious agents. Current FDA-approved antifibrotic drugs slow the progression of pulmonary fibrosis with limited outcomes in overall survival, highlighting the need for novel pharmacological agents. Ugonin L (UL), a cyclized geranylflavonoid derived from Helminthostachys zeylanica, has been reported to have anti-inflammatory and antioxidant activities. However, the therapeutic potential of UL for pulmonary fibrosis remains unexplored. In this study, we demonstrated that UL mitigated pulmonary fibrosis in bleomycin (BLM)-induced mice. Specifically, UL improved the alveolar-capillary barrier integrity, decreasing inflammatory cytokines (TGF-β1, TNF-α, IL-1β, IL-6) in bronchoalveolar lavage fluid (BALF). UL ameliorated lesions in BLM-induced fibrotic lungs, reducing radiological signs of lung injury, alveolar septal thickening, and collagen deposition. In RNA-seq analysis, UL downregulated genes related to cell migration and ECM remodeling in TGF-β1-induced LL29 human lung fibroblasts. In particular, UL decreased cell migration, fibrotic marker expression, MMP-2 activity, and myofibroblast activation. In molecular modeling, UL interacted with key pharmacophores and the putative ATP-binding sites of the TβRI and TβRII kinase domains. Correspondingly, UL reduced the phosphorylation of key mediators in both the canonical (SMAD2/3) and non-canonical (ERK1/2 and PI3K) TGF-β signaling pathways. Furthermore, UL downregulated the PI3K/Akt/mTOR axis and promoted autophagy in TGF-β1-induced LL29 cells. Taken together, our findings demonstrate that UL acts as a novel TβRs inhibitor and shows therapeutic potential for pulmonary fibrosis.

Keywords: Autophagy; Pulmonary fibrosis; TGF-β signaling; TβRs inhibitor; Ugonin L.