{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:07:53Z","timestamp":1792040873431,"version":"4.4.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"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><jats:title>Background and objective<\/jats:title><jats:p>Qinggan Yipi Capsule (QgYp) is a hospital preparation that has been used for many years in the treatment of chronic liver diseases. However, the mechanism of QgYp in ameliorating hepatic fibrosis (HF) remains unclear. This study aims to clarify the anti-liver fibrosis effect of QgYp and its mechanism of action.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study uses a carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) induced HF rat model and TGF-\u03b21 stimulated HSC-T6 cell line (rat HSCs) as experimental models. The therapeutic effects were evaluated through pathology, biochemical tests, and ELISA. The therapeutic mechanism of QgYp for HF was predicted through network pharmacology. The expression of TGF-\u03b21\/Smad2\/3 related proteins was detected by qPCR analysis and Western blot analysis. The composition of the gut microbiota was analyzed using 16S rRNA gene sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Histopathological analysis, serum biochemical tests, and ELISA measurements showed that QgYp effectively decreased the levels of ALT, AST, HA, LN, PCIII, and IV-C while improving collagen deposition and hepatocyte necrosis. Protein-protein interaction (PPI) network analysis screened HF-related genes, including peroxisome proliferator-activated receptor gamma (PPARG), tumor necrosis factor (TNF), and TGF-\u03b21. GO and KEGG analyses indicated that QgYp significantly affects TGF-\u03b2 signaling pathway. In addition, the results of qPCR and Western blot analysis from both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> experiments indicated that QgYp significantly downregulated the expression of proteins and mRNA associated with the TGF-\u03b21\/Smad2\/3 pathway. The 16S rDNA gene sequencing results showed that QgYp can increase the diversity and richness of the gut microbiota in HF rats and alter the composition of the gut microbiota.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>QgYp could effectively ameliorate HF, and this effect might be connected to the downregulation of the TGF-\u03b21\/Smad2\/3 pathway, the suppression of HSCs activation, and regulation of gut microbiota dysbiosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1525914","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T07:15:07Z","timestamp":1737702907000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Qinggan Yipi capsule ameliorates hepatic fibrosis in rats by down-regulating the TGF-\u03b21\/Smad2\/3 signaling pathway and improving gut microbiota imbalance"],"prefix":"10.3389","volume":"16","author":[{"given":"Wenjing","family":"Xue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiqing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziheng","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junping","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhi","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lurong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.5387\/fms.2019-21","article-title":"Gut and oral microbiota in autoimmune liver disease","volume":"65","author":"Abe","year":"2020","journal-title":"Fukushima J. Med. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/j.drudis.2021.12.012","article-title":"Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis","volume":"27","author":"Baghaei","year":"2022","journal-title":"Drug Discov. Today."},{"key":"B3","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1093\/toxsci\/kfs243","article-title":"A performance evaluation of three drug-induced liver injury biomarkers in the rat: alpha-glutathione S-transferase, arginase 1, and 4-hydroxyphenyl-pyruvate dioxygenase","volume":"130","author":"Bailey","year":"2012","journal-title":"Toxicol. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"6660","DOI":"10.3390\/ijms24076660","article-title":"Role of the gut\u2013liver Axis in the pathobiology of cholangiopathies: basic and clinical evidence","volume":"24","author":"Bragazzi","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1002\/hep.31056","article-title":"Increased liver localization of lipopolysaccharides in human and experimental NAFLD","volume":"72","author":"Carpino","year":"2020","journal-title":"Hepatology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/s0925-4439(00)00059-4","article-title":"Antioxidant properties of colchicine in acute carbon tetrachloride induced rat liver injury and its role in the resolution of established cirrhosis","volume":"1502","author":"Das","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1038\/s41591-019-0495-2","article-title":"Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study","volume":"25","author":"Depommier","year":"2019","journal-title":"Nat. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"947755","DOI":"10.3389\/fimmu.2022.947755","article-title":"Immunomodulatory effects of the Bifidobacterium longum BL-10 on lipopolysaccharide-induced intestinal mucosal immune injury","volume":"13","author":"Dong","year":"2022","journal-title":"Front. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"118893","DOI":"10.1016\/j.jep.2024.118893","article-title":"Qianggan Ruanjian Pill ameliorates liver fibrosis through regulation of the TGF-\u03b21\/Smad and PI3K\/AKT signalling pathways","volume":"337","author":"Feng","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"117163","DOI":"10.1016\/j.biopha.2024.117163","article-title":"Graveoline attenuates D-GalN\/LPS-induced acute liver injury via inhibition of JAK1\/STAT3 signaling pathway","volume":"177","author":"He","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13020-023-00745-5","article-title":"A novel microbial and hepatic biotransformation-integrated network pharmacology strategy explores the therapeutic mechanisms of bioactive herbal products in neurological diseases: the effects of Astragaloside IV on intracerebral hemorrhage as an example","volume":"18","author":"Hu","year":"2023","journal-title":"Chin. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"122380","DOI":"10.1016\/j.lfs.2023.122380","article-title":"Bile acids metabolism in the gut-liver axis mediates liver injury during lactation","volume":"338","author":"Huang","year":"2024","journal-title":"Life Sci."},{"key":"B13","volume-title":"Study on the mechanism of improving chronic renal injury by the damp-clearing Chinesemedicine through regulating RAS [master's thesis]","author":"Jingru","year":"2021"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.1113\/JP281061","article-title":"Hepatic stellate cells in physiology and pathology","volume":"600","author":"Kamm","year":"2022","journal-title":"J. Physiology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"705","DOI":"10.3390\/diagnostics10090705","article-title":"Photoacoustic imaging for assessing tissue oxygenation changes in rat hepatic fibrosis","volume":"10","author":"Karmacharya","year":"2020","journal-title":"Diagnostics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1056\/NEJM198806303182602","article-title":"Colchicine in the treatment of cirrhosis of the liver","volume":"318","author":"Kershenobich","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"118804","DOI":"10.1016\/j.jep.2024.118804","article-title":"Si-Ni-San ameliorates cholestatic liver injury by favoring P. goldsteinii colonization","volume":"337","author":"Li","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"792414","DOI":"10.3389\/fphar.2021.792414","article-title":"Resolvin D1 attenuates CCl4 induced liver fibrosis by inhibiting autophagy-mediated HSC activation via AKT\/mTOR pathway","volume":"12","author":"Li","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"3905130","DOI":"10.1155\/2020\/3905130","article-title":"Gut microbiota and liver fibrosis: one potential biomarker for predicting liver fibrosis","volume":"2020","author":"Li","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"B20","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.toxlet.2022.04.004","article-title":"The mouse Anxa6\/miR-9-5p\/Anxa2 axis modulates TGF-\u03b21-induced mouse hepatic stellate cell (mHSC) activation and CCl4-caused liver fibrosis","volume":"362","author":"Liao","year":"2022","journal-title":"Toxicol. Lett."},{"key":"B21","doi-asserted-by":"publisher","first-page":"917","DOI":"10.14218\/JCTH.2021.00032","article-title":"Indole-3-propionic acid-aggravated CCl4-induced liver fibrosis via the TGF-\u03b21\/smads signaling pathway","author":"Liu","year":"2021","journal-title":"J. Clin. Transl. Hepatol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2316923","DOI":"10.1080\/19490976.2024.2316923","article-title":"S-amlodipine induces liver inflammation and dysfunction through the alteration of intestinal microbiome in a rat model","volume":"16","author":"Liu","year":"2024","journal-title":"Gut Microbes"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2050","DOI":"10.1002\/hep.30975","article-title":"Probiotic Lactobacillus rhamnosus GG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice","volume":"71","author":"Liu","year":"2020","journal-title":"Hepatology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"4846","DOI":"10.21037\/apm-20-2129","article-title":"Traditional Chinese medicine, liver fibrosis, intestinal flora: is there any connection? a narrative review","volume":"10","author":"Liu","year":"2021","journal-title":"Ann. Palliat. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.jcmgh.2022.03.011","article-title":"Mannan-binding lectin via interaction with cell surface calreticulin promotes senescence of activated hepatic stellate cells to limit liver fibrosis progression","volume":"14","author":"Luo","year":"2022","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"155974","DOI":"10.1016\/j.phymed.2024.155974","article-title":"Lithospermic acid improves liver fibrosis through Piezo1-mediated oxidative stress and inflammation","volume":"134","author":"Luo","year":"2024","journal-title":"Phytomedicine"},{"key":"B27","doi-asserted-by":"publisher","first-page":"4108","DOI":"10.21037\/apm-20-1623","article-title":"Comparison of four markers of hepatic fibrosis and hepatic function indices in patients with liver cirrhosis and hepatoma","volume":"10","author":"Ma","year":"2021","journal-title":"Ann. Palliat. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"173578","DOI":"10.1016\/j.ejphar.2020.173578","article-title":"A comprehensive review of natural products to fight liver fibrosis: alkaloids, terpenoids, glycosides, coumarins and other compounds","volume":"888","author":"Ma","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"118925","DOI":"10.1016\/j.jep.2024.118925","article-title":"Protective effects of phenylethanol glycosides from Cistanche tubulosa against ALD through modulating gut microbiota homeostasis","volume":"337","author":"Qi","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"122","DOI":"10.13865\/j.cnki.cjbmb.2017.02.04","article-title":"TGF-\u03b21 receptor 1 and 2 in regulating cell proliferation by TGF-\u03b21","volume":"33","author":"Qiu-Shi","year":"2017","journal-title":"Chin. J. Biochem. Mol. Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"875","DOI":"10.3390\/cells9040875","article-title":"Liver fibrosis: mechanistic concepts and therapeutic perspectives","volume":"9","author":"Roehlen","year":"2020","journal-title":"Cells"},{"key":"B32","doi-asserted-by":"publisher","first-page":"105765","DOI":"10.1016\/j.intimp.2019.105765","article-title":"Research progress on the anti-hepatic fibrosis action and mechanism of natural products","volume":"75","author":"Shan","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"B33","first-page":"443","article-title":"The effect of Qingliyispleen capsule in 1000 HBsAg positive carriers","volume":"22","author":"Sl","year":"2002","journal-title":"J. Soochow Univ. Med. Ed."},{"key":"B34","volume-title":"Study on preparation technology optimization and quality standard of Qinggan Yipi capsule [master's thesis]","author":"Sq","year":"2022"},{"key":"B35","doi-asserted-by":"publisher","first-page":"615","DOI":"10.47162\/RJME.61.3.01","article-title":"Hepatic stellate cells \u2013 from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology","volume":"61","author":"Sufle\u0163el","year":"2021","journal-title":"Rom. J. Morphol. Embryol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.13381\/j.cnki.cjm.202212002","article-title":"Effect of indigo on intestinal flora in mice with ulcerative colitis induced by sodium dextran sulfate","volume":"34","author":"Ting","year":"2022","journal-title":"Chin. J. Microecology."},{"key":"B37","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3389\/fcimb.2020.00018","article-title":"Gut microbial dysbiosis is associated with profibrotic factors in liver fibrosis mice","volume":"10","author":"Wan","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"756924","DOI":"10.3389\/fphar.2021.756924","article-title":"Phillygenin attenuates carbon tetrachloride-induced liver fibrosis via modulating inflammation and gut microbiota","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"997","DOI":"10.7501\/j.issn.1674-6376.2022.05.025","article-title":"Research progress of pharmacologic effects and mechanism on ulcerative colitis of Indigo Naturalis and its active ingredients","volume":"45","author":"Xi","year":"2022","journal-title":"Drug Eval. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"8506","DOI":"10.1021\/acs.jafc.3c08541","article-title":"Theabrownin as a potential prebiotic compound regulates lipid metabolism via the gut microbiota, microbiota-derived metabolites, and hepatic FoxO\/PPAR signaling pathways","volume":"72","author":"Xiao","year":"2024","journal-title":"J. Agric. Food. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e38339","DOI":"10.1016\/j.heliyon.2024.e38339","article-title":"The impact of traditional Chinese medicine and dietary compounds on modulating gut microbiota in hepatic fibrosis: a review","volume":"10","author":"Xue","year":"2024","journal-title":"Heliyon"},{"key":"B42","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.toxlet.2021.06.021","article-title":"Ppic modulates CCl4-induced liver fibrosis and TGF-\u03b2-caused mouse hepatic stellate cell activation and regulated by miR-137-3p","volume":"350","author":"Yang","year":"2021","journal-title":"Toxicol. Lett."},{"key":"B43","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1248\/bpb.b17-00882","article-title":"Effects of oridonin on hepatic cytochrome P450 expression and activities in PXR-humanized mice","volume":"41","author":"Yi-Wen","year":"2018","journal-title":"Biol. Pharm. Bull."},{"key":"B44","doi-asserted-by":"publisher","first-page":"109838","DOI":"10.1016\/j.biopha.2020.109838","article-title":"Study on the anti-tumor mechanism related to immune microenvironment of Bombyx Batryticatus on viral and non-viral infections of hepatocellular carcinoma","volume":"124","author":"Yuan","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"B45","volume-title":"Study on the activity and drug formation of beauverine from Bombyx batryticatus [master's thesis]","author":"Yv","year":"2023"},{"key":"B46","doi-asserted-by":"publisher","first-page":"112714","DOI":"10.1016\/j.jep.2020.112714","article-title":"Hepatoprotective effect of total flavonoids of Mallotus apelta (Lour.) Muell.Arg. leaf against carbon tetrachloride-induced liver fibrosis in rats via modulation of TGF-\u03b21\/Smad and NF-\u03baB signaling pathways","volume":"254","author":"Zhang","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"4511","DOI":"10.3892\/ol.2017.6762","article-title":"Intestinal flora imbalance promotes alcohol-induced liver fibrosis by the TGF\u03b2\/smad signaling pathway in mice","volume":"14","author":"Zhang","year":"2017","journal-title":"Oncol. Lett."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2323236","DOI":"10.1080\/19490976.2024.2323236","article-title":"Multi-omics reveals deoxycholic acid modulates bile acid metabolism via the gut microbiota to antagonize carbon tetrachloride-induced chronic liver injury","volume":"16","author":"Zhang","year":"2024","journal-title":"Gut Microbes"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12272-014-0445-y","article-title":"Hepatoprotective effects of loach (Misgurnus anguillicaudatus) lyophilized powder on dimethylnitrosamine-induced liver fibrosis in rats","volume":"44","author":"Zhang","year":"2021","journal-title":"Arch. Pharm. Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"937484","DOI":"10.3389\/fphar.2022.937484","article-title":"Pien-Tze-Huang alleviates CCl4-induced liver fibrosis through the inhibition of HSC autophagy and the TGF-\u03b21\/Smad2 pathway","volume":"13","author":"Zhang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.jphs.2022.10.001","article-title":"Aronia melanocarpa polysaccharide ameliorates liver fibrosis through TGF-\u03b21-mediated the activation of PI3K\/AKT pathway and modulating gut microbiota","volume":"150","author":"Zhao","year":"2022","journal-title":"J. Pharmacol. Sci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.carbpol.2014.12.037","article-title":"Hypoglycemic activity and potential mechanism of a polysaccharide from the loach in streptozotocin-induced diabetic mice","volume":"121","author":"Zhou","year":"2015","journal-title":"Carbohydr. Polym."},{"key":"B53","doi-asserted-by":"publisher","first-page":"e0004722","DOI":"10.1128\/spectrum.00047-22","article-title":"Longitudinal 16S rRNA sequencing reveals relationships among alterations of gut microbiota and nonalcoholic fatty liver disease progression in mice","volume":"10","author":"Zhuge","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"B54","doi-asserted-by":"publisher","first-page":"501","DOI":"10.13286\/j.1001-5213.2023.05.06","article-title":"Comparative and self-healing study of two modeling methods in rat liver fibrosis model induced by intraperitoneal and subcutaneous injection of CCl4","volume":"43","author":"Ziheng","year":"2023","journal-title":"Chin. Hosp. Pharm. J."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1525914\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T07:15:16Z","timestamp":1737702916000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1525914\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,24]]},"references-count":54,"alternative-id":["10.3389\/fphar.2025.1525914"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1525914","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,24]]},"article-number":"1525914"}}