Ugonin L ameliorates pulmonary fibrosis as a novel TβRs inhibitor by regulating the TGF-β/TβRs signaling and autophagy

Le résumé fourni par la source

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown etiology, affecting about 3 million individuals worldwide. Significant risk factors for IPF include advanced age and infectious agents. Current FDA-approved antifibrotic drugs slow the progression of pulmonary fibrosis with limited outcomes in overall survival, highlighting the need for novel pharmacological agents. Ugonin L (UL), a cyclized geranylflavonoid derived from Helminthostachys zeylanica, has been reported to have anti-inflammatory and antioxidant activities. However, the therapeutic potential of UL for pulmonary fibrosis remains unexplored. In this study, we demonstrated that UL mitigated pulmonary fibrosis in bleomycin (BLM)-induced mice. Specifically, UL improved the alveolar-capillary barrier integrity, decreasing inflammatory cytokines (TGF-β1, TNF-α, IL-1β, IL-6) in bronchoalveolar lavage fluid (BALF). UL ameliorated lesions in BLM-induced fibrotic lungs, reducing radiological signs of lung injury, alveolar septal thickening, and collagen deposition. In RNA-seq analysis, UL downregulated genes related to cell migration and ECM remodeling in TGF-β1-induced LL29 human lung fibroblasts. In particular, UL decreased cell migration, fibrotic marker expression, MMP-2 activity, and myofibroblast activation. In molecular modeling, UL interacted with key pharmacophores and the putative ATP-binding sites of the TβRI and TβRII kinase domains. Correspondingly, UL reduced the phosphorylation of key mediators in both the canonical (SMAD2/3) and non-canonical (ERK1/2 and PI3K) TGF-β signaling pathways. Furthermore, UL downregulated the PI3K/Akt/mTOR axis and promoted autophagy in TGF-β1-induced LL29 cells. Taken together, our findings demonstrate that UL acts as a novel TβRs inhibitor and shows therapeutic potential for pulmonary fibrosis.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.