Page 228 - 2025中醫藥與天然藥物聯合學術研討會-中醫藥與天然藥物的挑戰Ｘ機遇與未來大會手冊

PP-46

Ugonin L ameliorates pulmonary fibrosis as a novel TβRs inhibitor by

regulating the TGF-β/TβRs signaling and autophagy

2,3
4,5
+,1
Tzu-Lan Hsia, Wei-Chung Chiou, Hsiu-Chen Huang, Hui-Kang Liu, Jui-Chieh
+,1
,1
Chen, Pin-Kuei Fu,* ,7,8,9 Cheng Huang*
6

1 Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming
Chiao Tung University, Taipei City 112304, Taiwan
2 Center for Teacher Education, National Tsing Hua University, Hsinchu City 300044,
Taiwan
3 Department of Applied Science, Nanda Campus, National Tsing Hua University, Hsinchu
City 300044, Taiwan
4 Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine,
Ministry of Health and Welfare, Taipei City 112304, Taiwan
5 Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy,
Taipei Medical University, Taipei City 110301, Taiwan
6 Department of Biochemical Science and Technology, National Chiayi University, Chiayi
600355, Taiwan
7 Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing
University, Taichung City 402010, Taiwan
8 Department of Medical Research, Taichung Veterans General Hospital, Taichung City
407219, Taiwan
9 Integrated Care Center of Interstitial Lung Disease, Taichung Veterans General Hospital,
Taichung City 407219, Taiwan
+ These authors contributed equally to this work
* E-mail: chengh@nycu.edu.tw

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