{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:26:16Z","timestamp":1790508376730,"version":"4.1.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Despite our previous findings that both total astragalus saponins (TAS) and hepatic AAV8.\n                      <jats:italic>Numb<\/jats:italic>\n                      -Exon3 overexpression (AAV8.\n                      <jats:italic>Numb<\/jats:italic>\n                      -Ex3\n                      <jats:sup>OE<\/jats:sup>\n                      ) are effective against cholestatic liver fibrosis (CLF), the synergistic effect and mechanism of their combination remain unknown. This study was designed to investigate this combination therapy and elucidate its underlying molecular mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A rat model of CLF was induced by bile duct ligation and subsequently treated with combination therapy. Evaluations included serum biochemical parameters, liver histopathology, hepatic hydroxyproline (Hyp) content, expression levels of key molecules in the Notch signaling pathway, hepatic progenitor cells (HPCs) differentiation, ductular reaction (DR), and liver regeneration.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , WB-F344 cells were induced toward a cholangiocyte-like phenotype, and the influence of TAS on HPCs differentiation was assessed following LV.\n                      <jats:italic>Numb<\/jats:italic>\n                      -Ex3 transfection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The combination therapy more effectively improved serum biochemistry, reduced hepatic inflammation and collagen deposition, and lowered hepatic Hyp content compared to TAS or AAV8.\n                      <jats:italic>Numb<\/jats:italic>\n                      -Ex3\n                      <jats:sup>OE<\/jats:sup>\n                      monotherapy. Mechanistically, the combination therapy further suppressed differentiation of HPCs into cholangiocytes and inhibited DR, while promoting HPC-to-hepatocyte differentiation and enhancing liver regeneration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The combination of TAS and AAV8.\n                      <jats:italic>Numb<\/jats:italic>\n                      -Ex3\n                      <jats:sup>OE<\/jats:sup>\n                      exerts a synergistic anti-fibrotic effect in CLF by redirecting HPCs differentiation fate. These findings provide experimental support for the development of novel combinatorial strategies against liver fibrosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1762397","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T05:38:14Z","timestamp":1776922694000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Synergistic amelioration of cholestatic liver fibrosis by combined total astragalus saponins and AAV8.Numb-Exon3 through modulation of hepatic progenitor cell differentiation"],"prefix":"10.3389","volume":"17","author":[{"given":"Mengyao","family":"Zong","sequence":"first","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannan","family":"Xu","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Xing","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrui","family":"Zheng","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyi","family":"Zhan","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamei","family":"Chen","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaofeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongping","family":"Mu","sequence":"additional","affiliation":[{"name":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41586-019-1373-2","article-title":"A human liver cell atlas reveals heterogeneity and epithelial progenitors","volume":"572","author":"Aizarani","year":"2019","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.molcel.2013.11.010","article-title":"RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation","volume":"52","author":"Bechara","year":"2013","journal-title":"Mol. Cell."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1002\/hep.24790","article-title":"Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol","volume":"55","author":"Chen","year":"2012","journal-title":"Hepatology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/nature06412","article-title":"NUMB controls p53 tumour suppressor activity","volume":"451","author":"Colaluca","year":"2008","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1083\/jcb.201709092","article-title":"A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of numb in breast cancer","volume":"217","author":"Colaluca","year":"2018","journal-title":"J. Cell. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3359","DOI":"10.1534\/g3.119.400494","article-title":"Exon 3 of the NUMB gene emerged in the chordate lineage coopting the NUMB protein to the regulation of MDM2","volume":"9","author":"Confalonieri","year":"2019","journal-title":"G3 (Bethesda)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1053\/jhep.2000.20240","article-title":"The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis","volume":"32","author":"Corpechot","year":"2000","journal-title":"Hepatology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/s41575-019-0156-4","article-title":"Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases","volume":"16","author":"Fabris","year":"2019","journal-title":"Nat. Reviews. Gastroenterol. Hepatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.3390\/ijms20061463","article-title":"A systematic review of phytochemistry, pharmacology and pharmacokinetics on astragali radix: implications for astragali radix as a personalized medicine","volume":"20","author":"Guo","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/0003-2697(81)90261-x","article-title":"A simple method to determine nanogram levels of 4-hydroxyproline in biological tissues","volume":"112","author":"Jamall","year":"1981","journal-title":"Anal. Biochem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1002\/hep.28367","article-title":"Differentiation therapy for hepatocellular carcinoma: multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis","volume":"63","author":"Jung","year":"2016","journal-title":"Hepatology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1083\/jcb.201712007","article-title":"Rewired Notch\/p53 by numb'ing Mdm2","volume":"217","author":"Kim","year":"2018","journal-title":"J. Cell. Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1055\/a-2097-0660","article-title":"HNF4\u03b1 in hepatocyte health and disease","volume":"43","author":"Kotulkar","year":"2023","journal-title":"Semin. Liver Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1172\/JCI88881","article-title":"Liver inflammation and fibrosis","volume":"127","author":"Koyama","year":"2017","journal-title":"J. Clin. Investig."},{"key":"B15","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/s41586-019-1531-6","article-title":"Asymmetric lysosome inheritance predicts activation of haematopoietic stem cells","volume":"573","author":"Loeffler","year":"2019","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1190827","DOI":"10.3389\/fendo.2023.1190827","article-title":"Total astragalus saponins can reverse type 2 diabetes mellitus-related intestinal dysbiosis and hepatic insulin resistance in vivo","volume":"14","author":"Ma","year":"2023","journal-title":"Front. Endocrinol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"109055","DOI":"10.1016\/j.cbi.2020.109055","article-title":"Cell fate, metabolic reprogramming and lncRNA of tumor-initiating stem-like cells induced by alcohol","volume":"323","author":"Machida","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"B18","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.molmed.2022.11.006","article-title":"Common mechanisms in pediatric acute liver failure","volume":"29","author":"Mann","year":"2023","journal-title":"Trends Mol. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1002\/hep.32405","article-title":"Mechanisms and molecules: what are the treatment targets for primary biliary cholangitis?","volume":"76","author":"Mayo","year":"2022","journal-title":"Hepatology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"23196","DOI":"10.1074\/jbc.M302827200","article-title":"Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain","volume":"278","author":"McGill","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1128\/MCB.00709-10","article-title":"Global profiling and molecular characterization of alternative splicing events misregulated in lung cancer","volume":"31","author":"Misquitta-Ali","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/labinvest.2009.123","article-title":"Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine-choline-deficient diet","volume":"90","author":"Mu","year":"2010","journal-title":"Lab. Investig."},{"key":"B23","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1056\/NEJMoa1509840","article-title":"A placebo-controlled trial of obeticholic acid in primary biliary cholangitis","volume":"375","author":"Nevens","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"20807","DOI":"10.1074\/jbc.M311396200","article-title":"A novel PTB-PDZ domain interaction mediates isoform-specific ubiquitylation of Mammalian numb","volume":"279","author":"Nie","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1038\/s41419-021-04263-w","article-title":"Loss of numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing notch signaling","volume":"12","author":"Shu","year":"2021","journal-title":"Cell. Death Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e168888","DOI":"10.1172\/JCI168888","article-title":"SPTAN1\/NUMB axis senses cell density to restrain cell growth and oncogenesis through hippo signaling","volume":"133","author":"Su","year":"2023","journal-title":"J. Clin. Investig."},{"key":"B27","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/0014-4827(84)90666-9","article-title":"A diploid epithelial cell line from normal adult rat liver with phenotypic properties of 'oval' cells","volume":"154","author":"Tsao","year":"1984","journal-title":"Exp. Cell. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/0092-8674(89)90849-0","article-title":"Numb, a gene required in determination of cell fate during sensory organ formation in drosophila embryos","volume":"58","author":"Uemura","year":"1989","journal-title":"Cell."},{"key":"B29","doi-asserted-by":"publisher","first-page":"17486","DOI":"10.1038\/s41598-020-74324-1","article-title":"Hepatic stem cell numb gene is a potential target of huang Qi decoction against cholestatic liver fibrosis","volume":"10","author":"Xu","year":"2020","journal-title":"Sci. Rep."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.3760\/cma.j.cn501113-20210222-00091","article-title":"Overexpression of numb gene can inhibit the progression of biliary liver fibrosis in adult liver","volume":"30","author":"Xu","year":"2022","journal-title":"Zhonghua Gan Zang Bing Za Zhi"},{"key":"B31","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s13287-023-03276-w","article-title":"BM-MSCs overexpressing the numb enhance the therapeutic effect on cholestatic liver fibrosis by inhibiting the ductular reaction","volume":"14","author":"Xu","year":"2023","journal-title":"Stem Cell. Res. Ther."},{"key":"B38","doi-asserted-by":"publisher","first-page":"39983","DOI":"10.1038\/s41598-025-23696-3","article-title":"Numb-exon3 and full length Numb equivalently alleviate cholestatic liver fibrosis by inhibiting ductular reaction","volume":"15","author":"Xu","year":"2025","journal-title":"Sci. Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1902","DOI":"10.1172\/JCI66369","article-title":"Hepatic stellate cells in liver development, regeneration, and cancer","volume":"123","author":"Yin","year":"2013","journal-title":"J. Clin. Investig."},{"key":"B33","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.jep.2015.04.015","article-title":"Astragaloside prevents BDL-Induced liver fibrosis through inhibition of notch signaling activation","volume":"169","author":"Yongping","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/labinvest.2015.149","article-title":"Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes","volume":"96","author":"Zhang","year":"2016","journal-title":"Lab. Investig."},{"key":"B35","doi-asserted-by":"publisher","first-page":"965914","DOI":"10.3389\/fphar.2022.965914","article-title":"Astragalus saponins and its main constituents ameliorate ductular reaction and liver fibrosis in a mouse model of DDC-Induced cholestatic liver disease","volume":"13","author":"Zhang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"116833","DOI":"10.1016\/j.jep.2023.116833","article-title":"Astragalus saponins protect against extrahepatic and intrahepatic cholestatic liver fibrosis models by activation of farnesoid X receptor","volume":"318","author":"Zhang","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e1004289","DOI":"10.1371\/journal.pgen.1004289","article-title":"The RNA-Binding protein QKI suppresses cancer-associated aberrant splicing","volume":"10","author":"Zong","year":"2014","journal-title":"PLoS Genet."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1762397\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T05:38:15Z","timestamp":1776922695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1762397\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,23]]},"references-count":38,"alternative-id":["10.3389\/fphar.2026.1762397"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1762397","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,23]]},"article-number":"1762397"}}