Work

Integrative network toxicology and pharmacology reveal that kaempferol alleviates BaP-triggered pulmonary fibrosis via suppressing Ras/COX-2-dependent cellular senescence

Year: 2026

Type: article

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.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1963570