{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T03:27:40Z","timestamp":1782703660560,"version":"3.54.5"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T00:00:00Z","timestamp":1750377600000},"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<\/jats:title><jats:p>Ginsenoside Re (G-Re), a unique ginsenoside almost exclusively found in Araliaceae plants, is a promising therapeutic agent for attenuating liver injury. This study aims to investigate the liver-protective effects of G-Re and the underlying mechanisms in acute liver injury models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male C57BL\/6 mice were intraperitoneally injected with various agents induce the acute liver injury model after pre-treatment with G-Re (5\u201320\u00a0mg\/kg, oral gavage). Additionally, the phosphoinositide 3-kinases (PI3K) inhibitor LY294002 and the mammalian target of rapamycin (mTOR) inhibitor RAPA were co-administered with G-Re in the thioacetamide (TAA)-induced rat hepatic stellate cell line (HSC-T6) to explore the mechanisms associated with G-Re.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>G-Re at (20\u00a0mg\/kg) protected liver against thioacetamide (TAA), ethanol, acetaminophen, and D-Galactosamine-induced liver injury in C57BL\/6 mice. G-Re reduced serum levels of aspartate aminotransferase (AST) from 151.98 to 40.24 U\/L and alanine aminotransferase (ALT) from 392.04 to 49.43 U\/L. Both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> studies consistently showed that G-Re decreased mRNA expression levels of key pro-inflammatory cytokines, including tumor necrosis factor-\u03b1 (TNF-\u03b1) and interleukin-1\u03b2 (IL-1\u03b2). Additionally, G-Re dose-dependently downregulated the protein expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), NOD-like receptor protein 3 (NLRP3), cysteinyl aspartate specific proteinase \u22121 (caspase-1), interleukin-18 (IL-18), and IL-1\u03b2. In addition, our results suggested that the suppression of autophagy by G-Re may play a crucial role in its ability to inhibit the NLRP3 inflammasome. Notably, this regulatory effect on autophagy appears to be mediated through the phosphatidylinositide 3-kinases\/protein kinase B\/mammalian target of rapamycin (PI3K\/AKT\/mTOR signaling pathway). G-Re inhibits autophagy in both cellular and animal models by downregulating the expression of light chain 3-II (LC3-II), Beclin-1, and sequestosome-1 (p62) through this pathway. Furthermore, the PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin (RAPA) were shown to partially reverse the inhibitory effects of G-Re on autophagy and inflammation in HSC-T6 cells. These results further support the notion that reactivation of autophagy can counteract G-Re\u2013mediated suppression of NLRP3 and caspase-1 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study highlights G-Re as a promising therapeutic candidate for liver injury, acting through inhibition of autophagy and inflammation via the PI3K\/AKT\/mTOR signaling pathway.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1592203","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T05:23:27Z","timestamp":1750397007000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Ginsenoside Re ameliorates thioacetamide-induced acute liver injury through inhibiting autophagy-NLRP3 inflammasome pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"Jing","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruowei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaohua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingqing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3109\/15569543.2013.805144","article-title":"An overview of thioacetamide-induced hepatotoxicity","volume":"32","author":"Akhtar","year":"2013","journal-title":"Toxin Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1111\/1751-2980.12918","article-title":"Role of NLRP3 inflammasome in liver disease","volume":"21","author":"AL Mamun","year":"2020","journal-title":"J. Dig. Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1093\/abbs\/gmz098","article-title":"Interaction between autophagy and the NLRP3 inflammasome","volume":"51","author":"Cao","year":"2019","journal-title":"ABBS"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7468","DOI":"10.1128\/AEM.01421-06","article-title":"Metabolism of thioamides by Ralstonia pickettii TA","volume":"72","author":"Dodge","year":"2006","journal-title":"Appl. Environ. Microbiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"4701","DOI":"10.1038\/emboj.2011.398","article-title":"Autophagy\u2010based unconventional secretory pathway for extracellular delivery of IL\u20101\u03b2","volume":"30","author":"Dupont","year":"2011","journal-title":"EMBO J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"754191","DOI":"10.3389\/fphar.2022.754191","article-title":"Pharmacological properties of ginsenoside re","volume":"13","author":"Gao","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.trecan.2020.08.005","article-title":"Cirrhosis: a questioned risk factor for hepatocellular carcinoma","volume":"7","author":"Garrido","year":"2021","journal-title":"Trends Cancer"},{"key":"B8","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.jnutbio.2016.12.011","article-title":"Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K\/AKT\/mTOR and STAT3 signaling pathways","volume":"41","author":"Granato","year":"2017","journal-title":"J. Nutr. Biochem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1053\/j.gastro.2011.12.044","article-title":"Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues","volume":"142","author":"Hern\u00e1NDEZ\u2013Gea","year":"2012","journal-title":"Gastroenterology"},{"key":"B10","doi-asserted-by":"publisher","first-page":"251","DOI":"10.23736\/S1121-421X.19.02596-0","article-title":"Human herpes viruses as cause of liver injury and acute liver failure","volume":"65","author":"Imperatrice","year":"2019","journal-title":"Minerva Gastroenterol. Dietol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.jgr.2022.11.002","article-title":"Ginsenoside re prevents 3-methyladenine-induced catagen phase acceleration by regulating Wnt\/\u03b2-catenin signaling in human dermal papilla cells","volume":"47","author":"Jeong","year":"2023","journal-title":"J. Ginseng Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"9003603","DOI":"10.1155\/2021\/9003603","article-title":"Ginsenoside re improves inflammation and fibrosis in hepatic tissue by upregulating PPAR\u03b3 expression and inhibiting oxidative stress in db\/db mice","volume":"2021","author":"Jiang","year":"2021","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"s104","DOI":"10.7861\/clinmedicine.16-6-s104","article-title":"Drug-induced liver injury","volume":"16","author":"Katarey","year":"2016","journal-title":"Clin. Med. (Lond)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.intimp.2014.02.009","article-title":"Protective effect of tormentic acid from Potentilla chinensis against lipopolysaccharide\/D-galactosamine induced fulminant hepatic failure in mice","volume":"19","author":"Lin","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"40568","DOI":"10.18632\/oncotarget.16501","article-title":"Glibenclamide, a diabetic drug, prevents acute radiation induced liver injury of mice via up-regulating intracellular ROS and subsequently activating Akt-NF-\u03baB pathway","volume":"8","author":"Liu","year":"2017","journal-title":"Oncotarget"},{"key":"B16","doi-asserted-by":"publisher","first-page":"5149417","DOI":"10.1155\/2020\/5149417","article-title":"Polyphyllin I promoted melanoma cells autophagy and apoptosis via PI3K\/Akt\/mTOR signaling pathway","volume":"2020","author":"Long","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/nature06639","article-title":"Autophagy fights disease through cellular self-digestion","volume":"451","author":"Mizushima","year":"2008","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1016\/j.jhep.2020.11.040","article-title":"Residual risk of liver disease after hepatitis C virus eradication","volume":"74","author":"Negro","year":"2021","journal-title":"J. Hepatol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.phrs.2012.07.003","article-title":"Targeting autophagy for the treatment of liver diseases","volume":"66","author":"Ni","year":"2012","journal-title":"Pharmacol. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: updated guidelines for reporting animal research","volume":"18","author":"Percie DU Sert","year":"2020","journal-title":"PLoS Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"73","DOI":"10.3892\/ijmm.2011.805","article-title":"Ginsenoside re lowers blood glucose and lipid levels via activation of AMP-activated protein kinase in HepG2 cells and high-fat diet fed mice","volume":"29","author":"Quan","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"B23","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1016\/j.toxrep.2021.04.011","article-title":"Drug-induced-acute liver failure: a critical appraisal of the thioacetamide model for the study of hepatic encephalopathy","volume":"8","author":"Sepehrinezhad","year":"2021","journal-title":"Toxicol. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"402","DOI":"10.3390\/horticulturae7100402","article-title":"Nanobiotechnological approaches to enhance potato resistance against potato leafroll virus (PLRV) using glycyrrhizic acid ammonium salt and salicylic acid nanoparticles","volume":"7","author":"Shoala","year":"2021","journal-title":"Horticulturae"},{"key":"B25","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1016\/j.intimp.2010.03.002","article-title":"Ginsenoside re enhances survival of human CD4+ T cells through regulation of autophagy","volume":"10","author":"Son","year":"2010","journal-title":"Int. Immunopharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1590\/s0102-86502006000700019","article-title":"Hepatic injury","volume":"21","author":"Stracieri","year":"2006","journal-title":"Acta Cir. Bras."},{"key":"B27","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1016\/j.jhep.2012.03.035","article-title":"Inflammasomes in liver diseases","volume":"57","author":"Szabo","year":"2012","journal-title":"J. Hepatol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1053\/j.gastro.2014.11.046","article-title":"Use of Hy's Law, R criteria, and nR criteria to predict acute liver failure or transplantation in patients with drug-induced liver injury","volume":"148","author":"Tansel","year":"2015","journal-title":"Gastroenterology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"953305","DOI":"10.3389\/fendo.2022.953305","article-title":"Protective effect of the curcumin-baicalein combination against macrovascular changes in diabetic angiopathy","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.3390\/cells8121597","article-title":"The upstream pathway of mTOR-mediated autophagy in liver diseases","volume":"8","author":"Wang","year":"2019","journal-title":"Cells"},{"key":"B31","first-page":"1","article-title":"New insights into Nod-like receptors (NLRs) in liver diseases","volume":"10","author":"Xu","year":"2018","journal-title":"Int. J. Physiol. Pathophysiol. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.rvsc.2019.04.016","article-title":"The PI3K\/Akt\/mTOR signaling pathway plays a role in regulating aconitine-induced autophagy in mouse liver","volume":"124","author":"Yang","year":"2019","journal-title":"Res. Vet. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"105388","DOI":"10.1016\/j.phrs.2020.105388","article-title":"Regulation of the NLRP3 inflammasome with natural products against chemical-induced liver injury","volume":"164","author":"Zou","year":"2021","journal-title":"Pharmacol. Res."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1592203\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T05:23:27Z","timestamp":1750397007000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1592203\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,20]]},"references-count":33,"alternative-id":["10.3389\/fphar.2025.1592203"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1592203","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,20]]},"article-number":"1592203"}}