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Updated: Aug 27, 2025
Unilateral Lung Volume Analysis Using Micro-CT for Enhanced Assessment of Pulmonary Fibrosis in Preclinical Models
Published on: June 20, 2025
Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis
Rui Wang1, Jian Xu2, Rong Yan1
1Clinical Research Institute, The First People's Hospital of Foshan, Foshan, China.
Abstract:
Transforming growth factor β receptor (TGF-β1R) and receptor tyrosine kinases (RTKs), such as VEGFRs, PDGFRs and FGFRs are considered important therapeutic targets in blocking myofibroblast migration and activation of idiopathic pulmonary fibrosis (IPF). To screen and design innovative prodrug to simultaneously target these four classes of receptors, we proposed an approach based on network pharmacology combining virtual screening and machine learning activity prediction, followed by efficient in vitro and in vivo models to evaluate drug activity. We first constructed Collagen1A2-A549 cells with type I collagen as the main biomarker and evaluated the activity of compounds to inhibit collagen expression at the cellular level. The data from the first round of Collagen1A2-A549 cell screening were substituted into the machine learning model, and the model was optimized accordingly. As a result, the false positive rate of the model was reduced from 85.0% to 66.7%, and two prospective compounds, Z103080500 and Z104578368, were finally selected. Collagen levels were reduced effectively by both Z103080500 (67.88% reduction) and Z104578368 (69.54% reduction). Moreover, these two compounds showed low cellular cytotoxicity. Subsequently, the effect of Z103080500 and Z104578368 was evaluated in a bleomycin-induced C57BL/6 mouse IPF model. These results showed that 50 mg/kg Z103080500 and Z104578368 could effectively reduce the number of inflammatory cells and the expression level of α-SMA. Meanwhile, Z103080500 and Z104578368 reduced the expression of major markers and inflammatory factors of IPF, such as collagen, IFN-γ, IL-17 and HYP, indicating that these screened Z103080500 and Z104578368 effectively delayed lung tissue inflammation and had a potential therapeutic effect on IPF. Our findings demonstrate that a screening and evaluation model for prodrug against IPF has been successfully established. It is of great significance to further modify these compounds to enhance their potency and activity.
Insights
Researchers developed a novel prodrug screening method targeting key receptors in idiopathic pulmonary fibrosis (IPF). Two compounds, Z103080500 and Z104578368, effectively reduced fibrosis markers and inflammation in preclinical models, showing therapeutic potential for IPF.
Area of Science:
- Pharmacology
- Drug Discovery
- Biomedical Engineering
Background:
- Idiopathic pulmonary fibrosis (IPF) involves myofibroblast activation driven by TGF-β1R and RTKs (VEGFRs, PDGFRs, FGFRs).
- Targeting these receptors is crucial for developing effective IPF therapies.
Purpose of the Study:
- To screen and design innovative prodrugs targeting TGF-β1R and RTKs simultaneously.
- To establish a robust screening and evaluation model for IPF prodrugs.
Main Methods:
- Network pharmacology combined with virtual screening and machine learning for drug prediction.
- In vitro evaluation using Collagen1A2-A549 cells to assess collagen expression inhibition.
- In vivo assessment in a bleomycin-induced C57BL/6 mouse model of IPF.
Main Results:
- Two compounds, Z103080500 and Z104578368, were identified, significantly reducing collagen levels (67.88% and 69.54% respectively) with low cytotoxicity.
- These compounds reduced inflammatory cell counts, α-SMA expression, and key IPF markers (collagen, IFN-γ, IL-17, HYP) in a mouse model.
- The developed screening model successfully reduced false positives and demonstrated efficacy.
Conclusions:
- A novel prodrug screening and evaluation model for IPF has been successfully established.
- Z103080500 and Z104578368 show significant therapeutic potential for IPF by mitigating lung inflammation and fibrosis.
- Further modification of these compounds could enhance their potency for IPF treatment.
