Machine Learning-Enabled Insights: Dihydromyricetin’s Novel Role in Inhibiting the TGF-β/ALK5 Signaling Cascade for the Treatment of Pulmonary Fibrosis

Luyao Dong; Wenting Dong; Yixin Ren; Chunjie Xu; Xiukun Wang; Peiyi Sun; Yao Meng; Congran Li; Guoqing Li; Jiandong Jiang; Hao Wang; Xuefu You; Xinyi Yang

doi:10.1016/j.eng.2025.10.017

Engineering ›› 2026, Vol. 58 ›› Issue (3) :258 -272. DOI: 10.1016/j.eng.2025.10.017

Research

Article

Machine Learning-Enabled Insights: Dihydromyricetin’s Novel Role in Inhibiting the TGF-β/ALK5 Signaling Cascade for the Treatment of Pulmonary Fibrosis

Luyao Dong ^a^,^b^,¹
, Wenting Dong ^a^,^b^,¹
, Yixin Ren ^c^,^d^,^e^,¹
, Chunjie Xu ^a^,^b
, Xiukun Wang ^a^,^b
, Peiyi Sun ^a^,^b
, Yao Meng ^a^,^b
, Congran Li ^a^,^b
, Guoqing Li ^a^,^b
, Jiandong Jiang ^f^,^g
, Hao Wang ^c^,^d^,^e^,^*
, Xuefu You ^a^,^h^,^*
, Xinyi Yang ^a^,^b^,^*

Author information +

^aBeijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

^bState Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

^cInstitute of National Security, Minzu University of China, Beijing 100081, China

^dSchool of Pharmacy, Minzu University of China, Beijing 100081, China

^eKey Laboratory of Ethnomedicine, Ministry of Education, Minzu University of China, Beijing 100081, China

^fState Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

^gInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

^hState Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

* E-mail address: hao.wang@muc.edu.cn

* E-mail address: xuefuyou@imb.pumc.edu.cn

* E-mail address: xinyiyang@imb.cams.cn

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Abstract

Idiopathic pulmonary fibrosis (IPF) denotes a chronic, advancing, and life-threatening lung disorder. Dysregulated cytokines, particularly those in the transforming growth factor-β (TGF-β)-associated signaling pathway, drive the pathological development of IPF. Natural products derived from traditional Chinese medicine hold great potential as promising therapeutic candidates for IPF. This study integrated machine learning (ML) with experimental validation to identify TGF-β/small mother against decapentaplegic (SMAD) pathway inhibitors from natural compounds. An in-house library was screened by means of a dual-luciferase reporter assay, revealing the flavonoid dihydromyricetin (DHM) as the most potent inhibitor. In vitro, DHM suppressed TGF-β1-triggered epithelial–mesenchymal transition (EMT) in A549 cells and fibroblast transdifferentiation in medical research council cell strain 5 (MRC-5) cells. In vivo, DHM attenuated fibrosis and inflammatory responses in a bleomycin (BLM)-triggered pulmonary fibrosis mouse model. Mechanistic studies revealed that DHM targets the type I TGF-β receptor (known as ALK5), reduces its membrane expression, binds directly to the receptor and represses its kinase activity, ultimately downregulating the TGF-β/ALK5 pathway. The present research is the first to report DHM as a TGF-β/SMAD inhibitor identified through ML with therapeutic efficacy against IPF. DHM’s anti-fibrotic effects are mediated through ALK5 blockade, suppressing downstream signaling, EMT, and fibroblast activation. These findings not only highlight DHM’s latent ability to act as a novel remedy for IPF but also underscore the utility of computational approaches in natural product drug discovery.

Keywords

Machine learning / Idiopathic pulmonary fibrosis / Fibroblast transdifferentiation / TGF-β signaling pathway / Dihydromyricetin / Type I TGF-β receptor

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Luyao Dong, Wenting Dong, Yixin Ren, Chunjie Xu, Xiukun Wang, Peiyi Sun, Yao Meng, Congran Li, Guoqing Li, Jiandong Jiang, Hao Wang, Xuefu You, Xinyi Yang. Machine Learning-Enabled Insights: Dihydromyricetin’s Novel Role in Inhibiting the TGF-β/ALK5 Signaling Cascade for the Treatment of Pulmonary Fibrosis. Engineering, 2026, 58(3): 258-272 DOI:10.1016/j.eng.2025.10.017

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