3,5,6,7,8,3’,4’- Heptamethoxyflavonoid inhibits TGF-β1-induced epithelial–mesenchymal transition by regulating oxidative stress and autophagy through MEK/ERK/PI3K/AKT/mTOR signaling pathway
Abstract Epithelial–mesenchymal transition (EMT) is a crucial pathological process in the pathogenesis of fibrosis. 3,5,6,7,8,3′,4′-hepmethoxyflavone (HMF), the main active ingredient extracted from the Chinese herb Breynia fruticosa (L.) Hook. f., has been shown to have beneficial effects on regula...
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Nature Portfolio
2025-02-01
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| author | Yiting Wang Zhiheng Ma Weiwen Peng Qinglian Yu Wenjie Liang Liu Cao Zhuqiang Wang |
| author_facet | Yiting Wang Zhiheng Ma Weiwen Peng Qinglian Yu Wenjie Liang Liu Cao Zhuqiang Wang |
| author_sort | Yiting Wang |
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| description | Abstract Epithelial–mesenchymal transition (EMT) is a crucial pathological process in the pathogenesis of fibrosis. 3,5,6,7,8,3′,4′-hepmethoxyflavone (HMF), the main active ingredient extracted from the Chinese herb Breynia fruticosa (L.) Hook. f., has been shown to have beneficial effects on regulating apoptosis and inhibiting collagen deposition. However, it remains unclear whether and how HMF alleviates transforming growth factor-β1 (TGF-β1)-induced EMT. The objective of this study was to investigate the impact of HMF on TGF-β1-induced EMT in human alveolar Type II epithelial cells (A549) and its underlying mechanism. In vitro culture of TGF-β1-induced EMT in A549 cells revealed that HMF reduced cell viability and migration, inhibited collagen deposition, decreased expression levels of mesenchymal cell markers and fibrosis markers α-SMA, MMP2, TIMP1, β-catenin, and Snail. Meanwhile, the expression level of E-cadherin increased as an epithelial cell marker. Additionally, we discussed the effects of HMF on oxidative stress and autophagy. Various experiments confirmed that HMF regulated the expression levels of Nrf2, keap-1, HO-1, ROS, MDA, SOD, GSH, and played a role in reducing oxidative stress. At the same time, HMF significantly activated autophagy by increasing expressions of Beclin-1 and LC3B as well as enhancing autophagosome content. The addition 3-MA, an autophagy inhibitor attenuated these beneficial effects. Furthermore, HMF significantly inhibited phosphorylation levels of MEK, ERK, PI3K, AKT, and mTOR through various pathways. In conclusion, HMF effectively inhibits TGF-β1-induced EMT in A549 cells by targeting the MEK/ERK/PI3K/AKT/mTOR signaling pathway. Moreover, it exhibits a close correlation with the suppression of oxidative stress and induction of autophagy. |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-67a46517ad554656828227b7d7b765202025-02-09T12:34:57ZengNature PortfolioScientific Reports2045-23222025-02-0115111310.1038/s41598-025-88869-63,5,6,7,8,3’,4’- Heptamethoxyflavonoid inhibits TGF-β1-induced epithelial–mesenchymal transition by regulating oxidative stress and autophagy through MEK/ERK/PI3K/AKT/mTOR signaling pathwayYiting Wang0Zhiheng Ma1Weiwen Peng2Qinglian Yu3Wenjie Liang4Liu Cao5Zhuqiang Wang6Department of Pharmacy, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese MedicineDepartment of Pharmacy, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese MedicineDepartment of Pharmacy, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese MedicineDepartment of Pharmacy, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese MedicineDepartment of Pharmacy, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese MedicineDepartment of Pharmacy, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese MedicineDepartment of Pharmacy, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese MedicineAbstract Epithelial–mesenchymal transition (EMT) is a crucial pathological process in the pathogenesis of fibrosis. 3,5,6,7,8,3′,4′-hepmethoxyflavone (HMF), the main active ingredient extracted from the Chinese herb Breynia fruticosa (L.) Hook. f., has been shown to have beneficial effects on regulating apoptosis and inhibiting collagen deposition. However, it remains unclear whether and how HMF alleviates transforming growth factor-β1 (TGF-β1)-induced EMT. The objective of this study was to investigate the impact of HMF on TGF-β1-induced EMT in human alveolar Type II epithelial cells (A549) and its underlying mechanism. In vitro culture of TGF-β1-induced EMT in A549 cells revealed that HMF reduced cell viability and migration, inhibited collagen deposition, decreased expression levels of mesenchymal cell markers and fibrosis markers α-SMA, MMP2, TIMP1, β-catenin, and Snail. Meanwhile, the expression level of E-cadherin increased as an epithelial cell marker. Additionally, we discussed the effects of HMF on oxidative stress and autophagy. Various experiments confirmed that HMF regulated the expression levels of Nrf2, keap-1, HO-1, ROS, MDA, SOD, GSH, and played a role in reducing oxidative stress. At the same time, HMF significantly activated autophagy by increasing expressions of Beclin-1 and LC3B as well as enhancing autophagosome content. The addition 3-MA, an autophagy inhibitor attenuated these beneficial effects. Furthermore, HMF significantly inhibited phosphorylation levels of MEK, ERK, PI3K, AKT, and mTOR through various pathways. In conclusion, HMF effectively inhibits TGF-β1-induced EMT in A549 cells by targeting the MEK/ERK/PI3K/AKT/mTOR signaling pathway. Moreover, it exhibits a close correlation with the suppression of oxidative stress and induction of autophagy.https://doi.org/10.1038/s41598-025-88869-63,5,6,7,8,3′,4′-HeptamethoxyflavonoidPulmonary fibrosisOxidative stressAutophagyEpithelial–mesenchymal transition |
| spellingShingle | Yiting Wang Zhiheng Ma Weiwen Peng Qinglian Yu Wenjie Liang Liu Cao Zhuqiang Wang 3,5,6,7,8,3’,4’- Heptamethoxyflavonoid inhibits TGF-β1-induced epithelial–mesenchymal transition by regulating oxidative stress and autophagy through MEK/ERK/PI3K/AKT/mTOR signaling pathway Scientific Reports 3,5,6,7,8,3′,4′-Heptamethoxyflavonoid Pulmonary fibrosis Oxidative stress Autophagy Epithelial–mesenchymal transition |
| title | 3,5,6,7,8,3’,4’- Heptamethoxyflavonoid inhibits TGF-β1-induced epithelial–mesenchymal transition by regulating oxidative stress and autophagy through MEK/ERK/PI3K/AKT/mTOR signaling pathway |
| title_full | 3,5,6,7,8,3’,4’- Heptamethoxyflavonoid inhibits TGF-β1-induced epithelial–mesenchymal transition by regulating oxidative stress and autophagy through MEK/ERK/PI3K/AKT/mTOR signaling pathway |
| title_fullStr | 3,5,6,7,8,3’,4’- Heptamethoxyflavonoid inhibits TGF-β1-induced epithelial–mesenchymal transition by regulating oxidative stress and autophagy through MEK/ERK/PI3K/AKT/mTOR signaling pathway |
| title_full_unstemmed | 3,5,6,7,8,3’,4’- Heptamethoxyflavonoid inhibits TGF-β1-induced epithelial–mesenchymal transition by regulating oxidative stress and autophagy through MEK/ERK/PI3K/AKT/mTOR signaling pathway |
| title_short | 3,5,6,7,8,3’,4’- Heptamethoxyflavonoid inhibits TGF-β1-induced epithelial–mesenchymal transition by regulating oxidative stress and autophagy through MEK/ERK/PI3K/AKT/mTOR signaling pathway |
| title_sort | 3 5 6 7 8 3 4 heptamethoxyflavonoid inhibits tgf β1 induced epithelial mesenchymal transition by regulating oxidative stress and autophagy through mek erk pi3k akt mtor signaling pathway |
| topic | 3,5,6,7,8,3′,4′-Heptamethoxyflavonoid Pulmonary fibrosis Oxidative stress Autophagy Epithelial–mesenchymal transition |
| url | https://doi.org/10.1038/s41598-025-88869-6 |
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