Areca catechu L. procyanidins alleviate pulmonary fibrosis by suppressing the TGF-β/Smad/ERK cascade: Validation of a traditional herbal medicine.

Areca nut has long been prescribed in Traditional Chinese Medicine for respiratory disorders resembling pulmonary fibrosis (PF). Its classical effects of resolving phlegm and dissipating chest stagnation, documented in Shennong Bencao Jing, align closely with PF's hallmark pathologies of interstitial scarring and excessive collagen accumulation, yet the mechanistic basis for its anti-fibrotic activity remains unelucidated. This study validated the anti-PF efficacy of areca nut procyanidins (ANP) and elucidated their multi-target mechanisms. A multi-faceted approach integrating network pharmacology, molecular docking, and in vivo/vitro experiments was employed. Rat PF models induced by bleomycin were treated with ANP (1, 5, 15 mg/kg) for 28 days. LPS-stimulated 3T6 fibroblasts were used to evaluate cellular mechanisms. Network pharmacology predicted 72 common targets, with enrichment in the TGF-β and MAPK pathways. Molecular docking confirmed strong binding affinity of ANP to TGF-β1 (-8.8 kcal/mol) and Smad3 (-6.8 kcal/mol). In vivo, medium- and high-dose ANP significantly ameliorated lung histopathology, reduced collagen deposition (HYP), and restored antioxidant biomarkers (T-AOC, MPO, GSH). Mechanistically, ANP concurrently suppressed the TGF-β/Smad/ERK signaling cascade, characterized by the downregulation of TGF-β1, p-Smad3/4, and p-ERK, alongside the restoration of the inhibitory Smad7. In vitro, ANP inhibited fibroblast migration, inflammation (IL-1β, TNF-α), and extracellular matrix production. By multi-target inhibition of the TGF-β/Smad/ERK cascade, ANP ameliorates PF, consistent with areca nut's traditional phlegm-resolving and nodule-dissipating properties. Compared with pirfenidone, ANP exhibits superior safety and multi-pathway activity, rendering it a promising botanical therapeutic agent for PF.