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Many studies have shown that the epithelial\u2013mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of pulmonary fibrosis. Based on our previous findings, hypericin (Hyp) can effectively inhibit the process of the EMT to attenuate lung fibrosis. Therefore, a series of hyperoside derivatives were synthesised via modifying the structure of hyperoside, and subsequently evaluated for A549 cytotoxicity. Among these, the pre-screening of eight derivatives inhibits the EMT. In this study, we evaluated the efficacy of Z6, the most promising hyperoside derivative, in reversing TGF-\u03b21-induced EMTs and inhibiting the EMT-associated migration of A549 cells. After the treatment of A549 cells with Z6 for 48 h, RT-qPCR and Western blot results showed that Z6 inhibited TGF-\u03b21-induced EMTs in epithelial cells by supressing morphological changes in A549 cells, up-regulating E-cadherin (p &lt; 0.01, p &lt; 0.001), and down-regulating Vimentin (p &lt; 0.01, p &lt; 0.001). This treatment significantly reduced the mobility of transforming growth factor \u03b21 (TGF-\u03b21)-stimulated cells (p &lt; 0.001) as assessed by wound closure, while increasing the adhesion rate of A549 cells (p &lt; 0.001). In conclusion, our results suggest that hyperoside derivatives, especially compound Z6, are promising as potential lead compounds for treating pulmonary fibrosis, and therefore deserve further investigation.<\/jats:p>","DOI":"10.3390\/ph17050584","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T07:04:14Z","timestamp":1714633454000},"page":"584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Structural Modification and Optimisation of Hyperoside Oriented to Inhibit TGF-\u03b2-Induced EMT Activity in Alveolar Epithelial Cells"],"prefix":"10.3390","volume":"17","author":[{"given":"Ziye","family":"Gao","sequence":"first","affiliation":[{"name":"Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhen","family":"Xu","sequence":"additional","affiliation":[{"name":"Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanguo","family":"Liu","sequence":"additional","affiliation":[{"name":"Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Gong","sequence":"additional","affiliation":[{"name":"Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yu","sequence":"additional","affiliation":[{"name":"Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaihui","family":"Lu","sequence":"additional","affiliation":[{"name":"Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixing","family":"Guan","sequence":"additional","affiliation":[{"name":"Experimental Center, Shandong Provincial Key Laboratory of Traditional Chinese Medicine, Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingjun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"},{"name":"Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1093\/abbs\/gmaa067","article-title":"Isoliquiritigenin inhibits TGF-\u03b21-induced fibrogenesis through activating autophagy via PI3K\/AKT\/mTOR pathway in MRC-5 cells","volume":"52","author":"He","year":"2020","journal-title":"Acta Biochim. 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