Nuciferine Inhibits Epithelial-Mesenchymal Transition (EMT) in A549 Cells and Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice via the TGF-β1/Smad2/3 Signaling Pathway.

Pulmonary fibrosis (PF) is a chronic inflammatory disorder marked by excessive extracellular matrix (ECM) deposition, leading to lung tissue scarring. This study explores nuciferine (NCF) as a potential therapeutic candidate for PF. In A549 cells, NCF (10 and 20 µM) maintained approximately 80% cell viability. TGF-β1 (5 ng/mL) was used to induce fibrosis, followed by treatment with NCF. Cell migration assays demonstrated that NCF significantly inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) and cell migration. At both concentrations, NCF markedly suppressed fibroblast activation. Male C57BL/6 mice were allocated into control, bleomycin (BLM, 2 U/kg), NCF (20 mg/kg and 40 mg/kg), and pirfenidone (PFD, 30 mg/kg) groups. NCF and PFD were administered orally for 21 days, starting on the day of BLM administration. Our results showed that NCF restores oxidative balance, enhances antioxidant levels, and decreases IL-6 levels in BLM-exposed lungs. Hematoxylin and eosin (H&E) staining revealed reduced alveolar and bronchiolar wall thickening with NCF, while collagen staining confirmed decreased collagen deposition. NCF modulated profibrotic proteins (α-SMA, CTGF, collagen I, fibronectin) and EMT markers (E-cadherin, N-cadherin, vimentin). In conclusion, NCF, a lotus-derived alkaloid with antioxidant properties, alleviates PF by inhibiting EMT, reducing inflammation, and restoring oxidative balance, highlighting its therapeutic potential.