Integrative network toxicology and pharmacology reveal that kaempferol alleviates BaP-triggered pulmonary fibrosis via suppressing Ras/COX-2-dependent cellular senescence
- 1Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine
- 2School of Chinese Medicine, Nanjing University of Chinese Medicine
Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease. Benzo[a]pyrene (BaP), a major constituent of cigarette smoke and air pollution, has been closely associated with pulmonary fibrosis. However, its molecular mechanism remains unclear. The natural flavonoid kaempferol possesses anti-inflammatory and antioxidant properties. However, its effects and mechanisms in BaP-induced pulmonary fibrosis remain unclear.
Objectives: This study aimed to predict potential targets of BaP-induced fibrosis and kaempferol intervention in BaP-induced IPF, and to validate whether kaempferol reverses BaP-induced epithelial senescence and fibrosis via the Ras/COX-2 signaling pathway in vitro .
Methods: Network toxicology, network pharmacology, machine learning, and molecular docking were integrated to predict potential targets of BaP-induced fibrosis and kaempferol intervention, followed by GO and KEGG pathway enrichment analyses. Additionally, virtual knockout analysis was performed to explore the regulatory relationships among Ras, COX-2, and cellular senescence. MLE-12 cells were used as an in vitro model, and senescence-related indicators were assessed by SA-β-gal staining, Western blot, and ELISA.
Results: KEGG enrichment analysis revealed that these targets were significantly enriched in the Ras signaling pathway. Molecular docking confirmed that kaempferol exhibited good binding affinity for the above target proteins. Cell experiments demonstrated that BaP significantly promoted cellular senescence and activated Ras and COX-2. Kaempferol treatment effectively reversed these changes.
Conclusion: This study reveals that BaP promotes IPF by inducing epithelial cell senescence via the Ras/COX-2 signaling pathway. Kaempferol may exert anti-fibrotic effects by counteracting this pathway-mediated senescence. These findings provide a theoretical basis for the pulmonary fibrosis effects of BaP and support kaempferol as a potential anti-fibrotic agent.
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BibTeX
@article{zhao2026integrative,
title = {{Integrative network toxicology and pharmacology reveal that kaempferol alleviates BaP-triggered pulmonary fibrosis via suppressing Ras/COX-2-dependent cellular senescence}},
author = {Qi Zhao and Dongwei Zhu and Zhichao Wu and Xiaolin Xia and Yehui Li and Aojie Guo and Yong Xu and Xianmei Zhou},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1963570},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1963570/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrative network toxicology and pharmacology reveal that kaempferol alleviates BaP-triggered pulmonary fibrosis via suppressing Ras/COX-2-dependent cellular senescence
AU - Qi Zhao
AU - Dongwei Zhu
AU - Zhichao Wu
AU - Xiaolin Xia
AU - Yehui Li
AU - Aojie Guo
AU - Yong Xu
AU - Xianmei Zhou
PY - 2026
DA - 2026/10/15
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1963570
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1963570/full
AB - Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease. Benzo[a]pyrene (BaP), a major constituent of cigarette smoke and air pollution, has been closely associated with pulmonary fibrosis. However, its molecular mechanism remains unclear. The natural flavonoid kaempferol possesses anti-inflammatory and antioxidant properties. However, its effects and mechanisms in BaP-induced pulmonary fibrosis remain unclear. Objectives: This study aimed to predict potential targets of BaP-induced fibrosis and kaempferol intervention in BaP-induced IPF, and to validate whether kaempferol reverses BaP-induced epithelial senescence and fibrosis via the Ras/COX-2 signaling pathway in vitro . Methods: Network toxicology, network pharmacology, machine learning, and molecular docking were integrated to predict potential targets of BaP-induced fibrosis and kaempferol intervention, followed by GO and KEGG pathway enrichment analyses. Additionally, virtual knockout analysis was performed to explore the regulatory relationships among Ras, COX-2, and cellular senescence. MLE-12 cells were used as an in vitro model, and senescence-related indicators were assessed by SA-β-gal staining, Western blot, and ELISA. Results: KEGG enrichment analysis revealed that these targets were significantly enriched in the Ras signaling pathway. Molecular docking confirmed that kaempferol exhibited good binding affinity for the above target proteins. Cell experiments demonstrated that BaP significantly promoted cellular senescence and activated Ras and COX-2. Kaempferol treatment effectively reversed these changes. Conclusion: This study reveals that BaP promotes IPF by inducing epithelial cell senescence via the Ras/COX-2 signaling pathway. Kaempferol may exert anti-fibrotic effects by counteracting this pathway-mediated senescence. These findings provide a theoretical basis for the pulmonary fibrosis effects of BaP and support kaempferol as a potential anti-fibrotic agent.
SN - 1663-9812
ER -