Phillyrin alleviates pulmonary fibrosis via modulation of the TGF-β1/Smad and Nrf2/HO-1 signaling pathways

Purpose: Pulmonary fibrosis (PF) is a fatal disease with limited treatment options. This study aimed to investigate the therapeutic potential of phillyrin (Phi), a bioactive compound derived from Forsythia suspensa, in treating PF and to explore its underlying mechanisms. Methods: A bleomycin (BLM)-induced murine PF model and TGF-β1-stimulated L929 fibroblasts were employed. Histopathological changes, collagen deposition, inflammatory cytokines (IL-1β, TNF-α), oxidative stress markers (MDA, SOD, GSH), and fibrotic proteins (α-SMA, COL1A1, etc.) were evaluated. Key signaling pathways, including Nrf2/HO-1 and TGF-β1/Smad2/3, were analyzed. Results: Phi significantly attenuated BLM-induced lung damage, collagen accumulation, and fibrosis scores (p < 0.001). It suppressed inflammation and oxidative stress by activating the Nrf2/HO-1 pathway. In TGF-β1-stimulated L929 cells, Phi inhibited proliferation, migration, invasion, and extracellular matrix (ECM) deposition. Furthermore, Phi attenuated TGF-β1-induced G2/M phase cell cycle arrest and reduced the levels of key fibrotic proteins. These effects were mediated through suppression of the TGF-β1/Smad2/3 pathway and epithelial-mesenchymal transition (EMT). Conclusion: Phi exerts anti-fibrotic, antioxidant, and anti-inflammatory effects by dual modulation of the TGF-β1/Smad2/3 and Nrf2 pathways, demonstrating significant therapeutic potential for pulmonary fibrosis. It is noteworthy that the in vitro evidence comes from L929 fibroblasts, and further validation in lung-relevant cell models would strengthen the translational relevance of these findings.