{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T17:59:19Z","timestamp":1791655159021,"version":"4.3.4"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2018,5,24]],"date-time":"2018-05-24T00:00:00Z","timestamp":1527120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatic stellate cell (HSC) activation is responsible for hepatic fibrogenesis and is associated with an overexpression of transcription 3 (STAT3). Luteolin, a common dietary flavonoid with potent anti-inflammatory properties, has previously demonstrated antifibrogenic properties in HSCs but the mechanism has not been fully elucidated. Activated human and rat hepatic stellate cell lines LX-2 and HSC-T6 were used to study the effects of luteolin on HSCs. Cellular proteins were determined by western blot and immunofluorescence. Cell proliferation was assessed with Alamar Blue assay. Luteolin significantly decreased LX-2 and HSC-T6 cell viability in a time-and-dose-dependent manner, as well as decreased HSC end-products \u03b1-smooth muscle actin (\u03b1-SMA), collagen I, and fibronectin. Luteolin decreased levels of total and phosphorylated STAT3, suppressed STAT3 nuclear translocation and transcriptional activity, and attenuated expression of STAT3-regulated proteins c-myc and cyclin D1. STAT3 specific inhibitors stattic and SH-4-54 demonstrated similar effects on HSC viability and \u03b1-SMA production. In LX-2 and HSC-T6 cells, luteolin demonstrates a potent ability to inhibit hepatic fibrogenesis via suppression of the STAT3 pathway. These results further elucidate the mechanism of luteolin as well as the effect of the STAT3 pathway on HSC activation.<\/jats:p>","DOI":"10.3390\/ijms19061567","type":"journal-article","created":{"date-parts":[[2018,5,24]],"date-time":"2018-05-24T07:54:01Z","timestamp":1527148441000},"page":"1567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Luteolin-Mediated Inhibition of Hepatic Stellate Cell Activation via Suppression of the STAT3 Pathway"],"prefix":"10.3390","volume":"19","author":[{"given":"Claire B.","family":"Cummins","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8272-8307","authenticated-orcid":false,"given":"Omar","family":"Nunez Lopez","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Graham","sequence":"additional","affiliation":[{"name":"School of Medicine, Alabama College of Osteopathic Medicine, Dothan, AL 36303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Yan","family":"Tie","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Basic Medicine, Zhengzhou University, Zhengzhou 450066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2811-1090","authenticated-orcid":false,"given":"Jia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi S.","family":"Radhakrishnan","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Roderfeld, M. (2017). Matrix metalloproteinase functions in hepatic injury and fibrosis. Matrix Biol.","DOI":"10.1016\/j.matbio.2017.11.011"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nature10237","article-title":"HIV-1 adaptation to NK-cell-mediated immune pressure","volume":"476","author":"Alter","year":"2011","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.bbadis.2013.02.019","article-title":"Origins and functions of liver myofibroblasts","volume":"1832","author":"Lemoinne","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.jhep.2010.11.035","article-title":"Inhibition of PDGF, TGF-beta, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib","volume":"55","author":"Liu","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1016\/j.bcp.2004.08.022","article-title":"Effects and regulation of osteopontin in rat hepatic stellate cells","volume":"68","author":"Lee","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/hep.22637","article-title":"Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment","volume":"49","author":"Ramm","year":"2009","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fang, S., Yuan, J., Shi, Q., Xu, T., Fu, Y., Wu, Z., and Guo, W. (2017). Downregulation of UBC9 promotes apoptosis of activated human LX-2 hepatic stellate cells by suppressing the canonical NF-kappaB signaling pathway. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174374"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/j.1440-1746.2011.07022.x","article-title":"Morphogens and hepatic stellate cell fate regulation in chronic liver disease","volume":"27","author":"Tsukamoto","year":"2012","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3389\/fphys.2012.00069","article-title":"Cytokines and STATs in Liver Fibrosis","volume":"3","author":"Kong","year":"2012","journal-title":"Front. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"536","DOI":"10.7150\/ijbs.7.536","article-title":"Signal transducer and activator of transcription 3 in liver diseases: A novel therapeutic target","volume":"7","author":"Wang","year":"2011","journal-title":"Int. J. Biol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jhep.2009.03.024","article-title":"Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK\/STAT and Akt\/NF-kappaB-dependent pathways","volume":"51","author":"Jiang","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1089\/ars.2010.3848","article-title":"Adipokines and redox signaling: Impact on fatty liver disease","volume":"15","author":"Parola","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7243","DOI":"10.1073\/pnas.1507499112","article-title":"Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition","volume":"112","author":"Su","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s10495-005-1055-4","article-title":"The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis","volume":"10","author":"Elsharkawy","year":"2005","journal-title":"Apoptosis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100652","DOI":"10.1039\/C6RA17459K","article-title":"STAT3 Inhibition Suppresses Hepatic Stellate Cell Fibrogenesis: HJC0123, a Potential Therapeutic Agent for Liver Fibrosis","volume":"6","author":"Bohanon","year":"2016","journal-title":"RSC Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.2174\/138955709787001712","article-title":"Distribution and biological activities of the flavonoid luteolin","volume":"9","year":"2009","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1093\/jn\/137.5.1244","article-title":"Estimated dietary flavonoid intake and major food sources of U.S. adults","volume":"137","author":"Chun","year":"2007","journal-title":"J. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.nutres.2010.07.001","article-title":"Reproducibility and relative validity of a food frequency questionnaire to assess intake of dietary flavonol and flavone in Chinese university campus population","volume":"30","author":"Zhang","year":"2010","journal-title":"Nutr. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1111\/liv.12638","article-title":"Antifibrotic effects of luteolin on hepatic stellate cells and liver fibrosis by targeting AKT\/mTOR\/p70S6K and TGFbeta\/Smad signalling pathways","volume":"35","author":"Li","year":"2015","journal-title":"Liver Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/S0091-3057(03)00108-4","article-title":"Salvia for dementia therapy: review of pharmacological activity and pilot tolerability clinical trial","volume":"75","author":"Perry","year":"2003","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.clinthera.2013.04.006","article-title":"An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders","volume":"35","author":"Taliou","year":"2013","journal-title":"Clin. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1111\/jphp.12812","article-title":"Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies","volume":"69","author":"Cao","year":"2017","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.3945\/jn.114.193128","article-title":"Luteolin alleviates alcoholic liver disease induced by chronic and binge ethanol feeding in mice","volume":"144","author":"Liu","year":"2014","journal-title":"J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5071","DOI":"10.7314\/APJCP.2014.15.12.5071","article-title":"Luteolin arrests cell cycling, induces apoptosis and inhibits the JAK\/STAT3 pathway in human cholangiocarcinoma cells","volume":"15","author":"Aneknan","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Fu, J., Chen, D., Zhao, B., Zhao, Z., Zhou, J., Xu, Y., Xin, Y., Liu, C., Luo, L., and Yin, Z. (2012). Luteolin induces carcinoma cell apoptosis through binding Hsp90 to suppress constitutive activation of STAT3. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049194"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.2147\/OTT.S91511","article-title":"Luteolin decreases invasiveness, deactivates STAT3 signaling, and reverses interleukin-6 induced epithelial-mesenchymal transition and matrix metalloproteinase secretion of pancreatic cancer cells","volume":"8","author":"Huang","year":"2015","journal-title":"OncoTargets Ther."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sonoki, H., Tanimae, A., Endo, S., Matsunaga, T., Furuta, T., Ichihara, K., and Ikari, A. (2017). Kaempherol and Luteolin Decrease Claudin-2 Expression Mediated by Inhibition of STAT3 in Lung Adenocarcinoma A549 Cells. Nutrients, 9.","DOI":"10.3390\/nu9060597"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e2612","DOI":"10.1038\/cddis.2017.38","article-title":"Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1","volume":"8","author":"Song","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.cbi.2014.02.002","article-title":"Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3","volume":"213","author":"Yang","year":"2014","journal-title":"Chem. Biol. Interact."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.bpg.2011.02.005","article-title":"Mechanisms of hepatic fibrogenesis","volume":"25","author":"Lee","year":"2011","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1172\/JCI66028","article-title":"Evolving therapies for liver fibrosis","volume":"123","author":"Schuppan","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.3892\/ijo.2014.2259","article-title":"The IL-6\/JAK\/STAT3 pathway: Potential therapeutic strategies in treating colorectal cancer (Review)","volume":"44","author":"Wang","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ejphar.2014.11.040","article-title":"The inhibition of activated hepatic stellate cells proliferation by arctigenin through G0\/G1 phase cell cycle arrest: Persistent p27(Kip1) induction by interfering with PI3K\/Akt\/FOXO3a signaling pathway","volume":"747","author":"Li","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Xiang, D.M., Sun, W., Ning, B.F., Zhou, T.F., Li, X.F., Zhong, W., Cheng, Z., Xia, M.Y., Wang, X., and Deng, X. (2017). The HLF\/IL-6\/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis. Gut.","DOI":"10.1136\/gutjnl-2016-313392"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kagan, P., Sultan, M., Tachlytski, I., Safran, M., and Ben-Ari, Z. (2017). Both MAPK and STAT3 signal transduction pathways are necessary for IL-6-dependent hepatic stellate cells activation. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176173"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.4049\/jimmunol.1401779","article-title":"Noncanonical STAT3 activation regulates excess TGF-beta1 and collagen I expression in muscle of stricturing Crohn\u2019s disease","volume":"194","author":"Li","year":"2015","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"34958","DOI":"10.1074\/jbc.M704548200","article-title":"Stat3 isoforms, alpha and beta, demonstrate distinct intracellular dynamics with prolonged nuclear retention of Stat3beta mapping to its unique C-terminal end","volume":"282","author":"Huang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1111\/febs.13285","article-title":"STAT3 the oncogene\u2014Still eluding therapy?","volume":"282","author":"Wake","year":"2015","journal-title":"FEBS J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.chembiol.2006.09.018","article-title":"Stattic: A small-molecule inhibitor of STAT3 activation and dimerization","volume":"13","author":"Schust","year":"2006","journal-title":"Chem. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1021\/ml4003138","article-title":"Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma","volume":"4","author":"Haftchenary","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.bbadis.2014.07.025","article-title":"Stat3 signaling activation crosslinking of TGF-beta1 in hepatic stellate cell exacerbates liver injury and fibrosis","volume":"1842","author":"Xu","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.1038\/sj.onc.1209281","article-title":"Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production","volume":"25","author":"Ogata","year":"2006","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.jhep.2012.01.029","article-title":"STAT proteins\u2014Key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver","volume":"57","author":"Gao","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1053\/j.gastro.2010.02.049","article-title":"Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis","volume":"138","author":"Mair","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.2353\/ajpath.2010.090469","article-title":"Lack of glycoprotein 130\/signal transducer and activator of transcription 3-mediated signaling in hepatocytes enhances chronic liver injury and fibrosis progression in a model of sclerosing cholangitis","volume":"176","author":"Plum","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1002\/hep.25744","article-title":"Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice","volume":"56","author":"Kong","year":"2012","journal-title":"Hepatology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/hep.510250218","article-title":"Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide","volume":"25","author":"Casini","year":"1997","journal-title":"Hepatology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/hep.20051","article-title":"Apoptosis: The nexus of liver injury and fibrosis","volume":"39","author":"Canbay","year":"2004","journal-title":"Hepatology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1055\/s-2001-17555","article-title":"Interactions between hepatic stellate cells and the immune system","volume":"21","author":"Maher","year":"2001","journal-title":"Semin. Liver Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jss.2014.03.036","article-title":"Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis","volume":"190","author":"Bohanon","year":"2014","journal-title":"J. Surg. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/6\/1567\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:05:47Z","timestamp":1760195147000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/6\/1567"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,24]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["ijms19061567"],"URL":"https:\/\/doi.org\/10.3390\/ijms19061567","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,24]]}}}