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Although existing studies have documented its hepatoprotective effects, the bioactive compounds and underlying mechanisms responsible for its anti\u2010hepatic fibrosis (HF) activity remain poorly understood. In this study, total flavonoids from\n                    <jats:italic>H. dulcis<\/jats:italic>\n                    seeds (\n                    <jats:italic>H. dulcis<\/jats:italic>\n                    total flavonoid [HDTF]) were purified using macroporous resin D101 and analyzed by ultra\u2010performance liquid chromatography\u2013Orbitrap\u2013mass spectrometry (UPLC\u2013Orbitrap\u2013MS). The model of HF was established by mice induced by CCl\n                    <jats:sub>4<\/jats:sub>\n                    and hepatic stellate cells (HSCs) stimulated with transforming growth factor\u2010\u03b21 (TGF\u2010\u03b21) to evaluate the anti\u2010hepatic fibrotic effects of HDTF. A combination of Cell Counting Kit\u20108 (CCK\u20108) assay, Western blot, wound\u2010healing assay, immunofluorescence staining, molecular docking, and confirmatory experiments was employed to elucidate the mechanisms involving the phosphoinositide 3\u2010kinase (PI3K)\/AKT pathway in the treatment of HF. As a result, 58 flavonoids were identified in the HDTF extracts. In both CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010induced liver injury in mice and TGF\u2010\u03b21\u2010activated HSCs, HDTF significantly attenuated HF by inhibiting HSC proliferation and migration. It also reduced the expression of \u03b1\u2010smooth muscle actin (\u03b1\u2010SMA) and Collagen I (COL\u2010I) in hepatic tissues and cell cultures, highlighting its anti\u2010fibrotic potential. Furthermore, HDTF decreased oxidative stress markers, including glutathione (GSH) and superoxide dismutase (SOD). Mechanistically, HDTF promoted apoptosis by modulating the expression of cleaved\u2010caspase\u20103 and phosphorylated AKT (p\u2010AKT). It also inhibited the PI3K\/AKT signaling pathway by reducing the levels of p\u2010AKT and phosphorylated PI3K (p\u2010PI3K), both in vivo and in vitro. This study demonstrates that HDTF ameliorates HF by inhibiting proliferation and promoting apoptosis through the PI3K\/AKT signaling pathway. These findings provide valuable insights into the therapeutic potential of\n                    <jats:italic>H. dulcis<\/jats:italic>\n                    seeds in the management of HF.\n                  <\/jats:p>","DOI":"10.1002\/cbdv.202502088","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T19:37:46Z","timestamp":1761334666000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Total Flavonoids of\n                    <i>Hovenia dulcis<\/i>\n                    Seeds Ameliorate Hepatic Fibrosis via Modulating PI3K\/AKT Signaling Pathway In Vitro and In Vivo"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1606-3407","authenticated-orcid":false,"given":"Jianzhan","family":"Yang","sequence":"first","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongning","family":"Shen","sequence":"additional","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Wu","sequence":"additional","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Fu","sequence":"additional","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine  Guangzhou China"},{"name":"Chinese Medicine Guangdong Laboratory  Zhuhai China"},{"name":"State Key Laboratory of Dampness Syndrome of Chinese Medicine  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8651-9329","authenticated-orcid":false,"given":"Fangfang","family":"Xu","sequence":"additional","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Research on Emergency in TCM  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2014.41"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010015\u20101543\u20104"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423\u2010023\u201000983\u20105"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu10070855"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.105222"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2012.12.020"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep03470"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.11607"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986712803341520"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.131097"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbdv.202201110"},{"key":"e_1_2_9_10_1","first-page":"941","article-title":"Review of Diagnostic Techniques of Hepatic Fibrosis","volume":"64","author":"Hassan S.","year":"2014","journal-title":"Journal of the Pakistan Medical Association"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharep.2017.11.017"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S194787"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2016.03.002"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010020\u201000372\u20107"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2003.50291"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.06.060"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.03.039"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0192415X07005181"},{"key":"e_1_2_9_19_1","first-page":"1097","article-title":"Effect of Hovenia Dulcis Extract on Expression of MMP\u201013 and TIMP\u20101 in Hepatic Tissue","volume":"31","author":"Liu X. 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