Combined Network Pharmacology, Transcriptomics and Machine Learning Suggests Danggui Buxue Tang May Suppress Oxidative Stress and Inflammation through Nrf2/HO-1 and IL-17 Pathways in Pulmonary Fibrosis.

ETHNOPHARMACOLOGICAL RELEVANCE Danggui Buxue Tang (DBT), a classical Chinese herbal formula of Astragalus membranaceus (Fisch.) Bunge and Angelica sinensis (Oliv.) Diels in a 5:1 ratio, has long been used for qi and blood deficiency. Its mechanism against pulmonary fibrosis (PF) remains unclear.

Aim

OF THE STUDY This study examined how DBT treats silica-induced PF, combining network pharmacology, transcriptomics, machine learning and experimental validation.

Materials And Methods

We built a rat PF model by intratracheal silica instillation. Network pharmacology and weighted gene co-expression network analysis (WGCNA) identified candidate therapeutic targets. Four machine learning algorithms screened diagnostic signature genes (DSGs). We profiled immune infiltration with CIBERSORT, modeled compound-target binding by molecular docking, and confirmed key genes and pathways by Western blotting.

Results

DBT treatment significantly attenuated silica-induced lung pathology, evidenced by improved pulmonary function, reduced alveolitis and fibrosis scores, diminished collagen deposition, and downregulated expression of α-smooth muscle actin, collagen I, and fibronectin. Furthermore, DBT markedly suppressed inflammatory responses (decreasing TNF-α, IL-6, IL-1β, and TGF-β1 while elevating IL-10) and mitigated oxidative stress (lowering MDA levels while enhancing SOD, GSH-Px, and T-AOC activities). Bioinformatic analyses identified three core DSGs-MMP7, MMP13, and TNF-as candidate therapeutic targets. Enrichment analyses highlighted the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and IL-17 signaling as the primary mechanistic routes. Immune profiling revealed that DBT's therapeutic effects correlate with specific shifts in immune cell subsets. Ultra-performance liquid chromatography-quadrupole-orbitrap mass spectrometry detected 11 prototype constituents in serum; notably, the Ononin, Methylnissolin-3-O-glucoside, and Isomucronulatol-7-O-glucoside exhibited strong binding affinities to MMP7, MMP13, and TNF. DBT inhibited the profibrotic IL-17 cascade while activating the antioxidant Nrf2/HO-1 axis.

Conclusion

Our data suggest that DBT may ease silica-induced PF through multiple targets that act on oxidative stress and inflammation. The DSGs (MMP7, MMP13, TNF) and pathways (Nrf2/HO-1, IL-17) help explain how DBT works and point to new targets for treating PF. The approach also provides a reusable workflow for studying other complex herbal formulas in fibrosis.