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Although pulmonary fibrosis (PF) causes respiratory failure and death, effective therapies for PF have not been developed. Oxymatrine (OMT), an active ingredient in the Chinese herb Sophora flavescens, exerts antifibrotic effects; however, its effect on PF remains unclear. The present study aimed to determine whether OMT decreases transforming growth factor-β1 (TGF-β1)-induced PF in human lung cancer A549 cells by inhibiting apoptosis and targeting the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. To construct a PF cell model, A549 cells were stimulated with TGF-β1. The experimental groups were as follows: control (untreated cells grown in complete medium), TGF-β1 (cells treated with 5 ng/ml TGF-β1), OMT (cells treated with 5 ng/ml TGF-β1 and 0.25, 0.50, or 1.00 mg/ml OMT), and OMT + LY294002 (cells treated with 5 ng/ml TGF-β1, 1.0 mg/ml OMT. and 25 µmol/l LY294002). The effects of OMT on cell morphology (via electron microscopy), apoptosis (via Annexin V-PI staining), mitochondrial apoptosis signaling [using JC-1 method to analyze mitochondrial membrane potential (MMP)], and Bcl-2, as well as Bax expression (via western blotting and reverse transcription-quantitative polymerase chain reaction), were analyzed. OMT significantly protected cells against TGF-β1-induced PF by inhibiting apoptosis. The specific manifestations were cell injury, as evidenced by morphological changes and decreased MMP. Following OMT treatment, the expression of the pro-apoptotic protein Bax increased, whereas that of the anti-apoptotic protein Bcl-2 decreased. The PI3K/AKT-specific inhibitor LY294002 significantly inhibited the ameliorative effects of OMT on TGF-β1-induced apoptosis. Collectively, OMT attenuated TGF-β1-mediated mitochondrial apoptosis of alveolar epithelial cells by activating the PI3K/AKT signaling pathway. Therefore, OMT may be a promising drug for PF treatment. [ABSTRACT FROM AUTHOR]