UL ameliorates lung inflammation and pulmonary fibrosis by regulating the TGF-β/TβRs signaling and autophagy

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Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disorder that affects 3 million people worldwide. It is characterized by aberrant activation of myofibroblasts and excessive extracellular matrix (ECM) deposition. Current IPF drugs pirfenidone and nintedanib have shown limited outcomes and potential side effects. Acute lung injury (ALI), persistent inflammation, age, pollutants, and infectious agents are known risk factors for IPF development and progression. Aims: Ugonin L (UL) is a cyclized geranylflavonoid with anti-inflammatory and antioxidant activities. This study investigated the therapeutic potential of UL for pulmonary inflammation and fibrosis. Methods: Murine models of lipopolysaccharide (LPS)-induced lung injury and bleomycin (BLM)-induced pulmonary fibrosis were used to study pathological changes in the lungs. LL29 human lung fibroblasts (HLF) were used to elucidate the effect of UL on TGF-β1-induced myofibroblast activation. Results: UL improved the overall survival of LPS- or BLM-challenged mice. Specifically, UL decreased inflammatory cell infiltration in LPS-induced lung injury. Meanwhile, UL improved lung architecture in BLM-induced PF. Mechanistically, UL mediated TGF-β/TβRs signaling by modulating TβRI and TβRII phosphorylation in TGF-β1-induced LL29 HLF. Meanwhile, UL promoted autophagy by PI3K/Akt/mTOR signaling. Besides, UL interacted with the putative ATP-binding domains of TβRI and TβRII in molecular modeling. Conclusion: UL has shown therapeutic potential for pulmonary inflammation and fibrosis by modulating TGF-β/TβRs signaling and autophagy.

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