Maimendong decoction and its active ingredient, ophiopogonin D, alleviate bleomycin-induced pulmonary fibrosis by regulating the behavior of lung fibroblasts

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive scarring of lung tissue, which can lead to respiratory failure and other serious complications, making the search for safe and effective therapeutic agents an urgent priority; Maimendong Decoction (MMDD), a traditional Chinese herbal formula widely employed in clinical practice to treat pulmonary disorders, has been shown to reduce inflammatory cytokines, suppress pro-fibrotic factors, and alleviate oxidative stress, yet the precise mechanisms by which MMDD exerts its anti-fibrotic effects remain unclear. This study aims to evaluate the therapeutic efficacy of MMDD in pulmonary fibrosis and to elucidate its underlying mechanisms. Using a bleomycin (BLM)-induced mouse model of idiopathic pulmonary fibrosis, we assessed the therapeutic impact of MMDD on pulmonary fibrosis; concurrently, Ophiopogonin-D (OP-D), a principal active ingredient of MMDD, was evaluated in an in vitro human fetal lung fibroblast model treated with transforming growth factor-β (TGF-β) to elucidate its precise anti-fibrotic mechanism; finally, multi-omics technologies and bioinformatics analyses were employed for comprehensive validation. MMDD ameliorated the degeneration observed in BLM-induced pulmonary fibrosis by curbing fibroblast activation and the over-deposition of extracellular matrix. Comprehensive multi-omics and bioinformatics analyses further indicated that MMDD modulates fibroblast behaviors-including proliferation and ferroptosis-through inhibition of the TGF-β signaling pathway. In vitro studies showed that OP-D induces ferroptosis in TGF-β-treated lung fibroblasts by blocking the negative regulatory signals of ferroptosis, mainly via downregulation of Ferritin Heavy Chain 1 (FTH1) expression. Moreover, overexpressing FTH1 nullified the anti-fibrotic activity of OP-D. The results of this study indicate that MMDD and its active component, OP-D, can treat IPF by targeting the proliferation of lung fibroblasts.