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Studies have recently identified a number of flavonoids with variable structures that have the potency of inhibiting collagen synthesis and thus attenuating organ fibrosis. In this study, we found that flavones with 5, 7, 3\u2032, 4\u2032 hydroxy substitution reduced collagen expression most efficiently. Among those flavones, luteolin, quercetin, and myricetin were selected for follow-up. In vivo, the three compounds ameliorated skin fibrosis and reduced collagen deposition. Further analysis showed the compounds had significant inhibition on the proliferation, activation and contractile ability of dermal fibroblasts in vitro and in vivo. More importantly, we revealed that luteolin, quercetin, and myricetin selectively downregulated the phosphorylation of Smad2\/3 in TGF-\u03b2\/Smads signaling via binding to activin receptor-like kinase 5 (ALK5) and impairing its catalytic activity. We also found flavones with 5, 7, 3\u2032, 4\u2032 hydroxy substitution showed stronger affinity with ALK5 compared with other flavonoids. Herein, we identified at least in part the underlying molecular basis as well as the critical structures that contribute to the antifibrotic bioactivity of flavones, which might benefit drug design and modification.<\/jats:p>","DOI":"10.1038\/s41419-019-1333-7","type":"journal-article","created":{"date-parts":[[2019,2,11]],"date-time":"2019-02-11T12:06:00Z","timestamp":1549886760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Flavones hydroxylated at 5, 7, 3\u2032 and 4\u2032 ameliorate skin fibrosis via inhibiting activin receptor-like kinase 5 kinase activity"],"prefix":"10.1038","volume":"10","author":[{"given":"Yifan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sizheng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibo","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuandong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,11]]},"reference":[{"key":"1333_CR1","doi-asserted-by":"publisher","first-page":"aaa2151","DOI":"10.1126\/science.aaa2151","volume":"348","author":"Y Rinkevich","year":"2015","unstructured":"Rinkevich, Y. et al. 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