{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T12:23:01Z","timestamp":1792498981407,"version":"4.5.0"},"reference-count":48,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Chronic liver damage usually results in a pathological state of excessive deposition of extracellular matrix that is known as liver fibrosis. This study was designed to examine the potential preventive effect of the pentahydroxyglucosyl flavone, gossypin (GPN), against concanavalin A (Con A)-induced liver fibrosis in BALB\/c albino mice. Methods: Liver fibrosis was induced by intravenous (IV) injection of Con A (10 mg\/kg) once weekly for 4 weeks. GPN (10 and 20 mg\/kg) was administered orally three times weekly for 4 weeks. At the end of the experiment, serum and liver tissue were obtained and used for different biochemical, histological, histochemical and molecular assessments. GPN (10 and 20 mg\/kg) considerably ameliorated liver fibrosis induced by Con A. A marked decrease in serum levels of ALT, AST and LDH was observed upon GPN treatment, confirmed by histopathological analysis by H&amp;E. GPN markedly reduced collagen deposition as confirmed by MT staining, reduced hepatic levels of Col-1 and TGF-\u03b2 as well as inhibited \u03b1-SMA immunostaining. The hepatic oxidative stress biomarker, MDA, was markedly reduced, whereas hepatic antioxidant defense, TAC, was significantly enhanced. Furthermore, GPN effectively enhanced gene and protein expression of SIRT3. GPN downregulated hepatic proinflammatory biomarkers, NF-\u03baB and TNF-\u03b1. Additionally, GPN caused a noticeable increase in the hepatic levels and expression of PI3K and Akt. GPN effectively attenuated Con A-induced liver fibrosis via reducing liver damage and collagen deposition majorly by lessening inflammation, oxidative stress and fibrosis. GPN modulated SIRT3, NF-\u03baB\/TNF-\u03b1 and PI3K\/Akt pathways.<\/jats:p>","DOI":"10.3390\/toxins18020074","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T10:03:29Z","timestamp":1770113009000},"page":"74","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SIRT3, NF-\u03baB\/TNF-\u03b1 and PI3K\/Akt Pathways Mediate the Hepatoprotective Activity of Gossypin Against Concanavalin A-Induced Hepatic Fibrosis"],"prefix":"10.3390","volume":"18","author":[{"given":"Hani M.","family":"Alrawili","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9528-7483","authenticated-orcid":false,"given":"Mahmoud","family":"Elshal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7185-5378","authenticated-orcid":false,"given":"Marwa S.","family":"Serrya","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7545-6235","authenticated-orcid":false,"given":"Dina S.","family":"El-Agamy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0168-8278(02)00413-0","article-title":"A comparison of fibrosis progression in chronic liver diseases","volume":"38","author":"Poynard","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"876","DOI":"10.5858\/arpa.2014-0214-RA","article-title":"Drug-induced liver injury","volume":"139","author":"Fisher","year":"2015","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hora, S., and Wuestefeld, T. (2023). Liver injury and regeneration: Current understanding, new approaches, and future perspectives. Cells, 12.","DOI":"10.3390\/cells12172129"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jhep.2018.03.011","article-title":"A simple diet-and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer","volume":"69","author":"Tsuchida","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, F.-D., Zhou, J., and Chen, E.-Q. (2022). Molecular mechanisms and potential new therapeutic drugs for liver fibrosis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.787748"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mam.2018.09.002","article-title":"Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues","volume":"65","author":"Parola","year":"2019","journal-title":"Mol. Aspects Med."},{"key":"ref_7","first-page":"361","article-title":"Molecular pathogenesis of liver fibrosis","volume":"120","author":"Brenner","year":"2009","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/cr.2008.328","article-title":"Non-Smad pathways in TGF-\u03b2 signaling","volume":"19","author":"Zhang","year":"2009","journal-title":"Cell Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Shamsan, E., Almezgagi, M., Gamah, M., Khan, N., Qasem, A., Chuanchuan, L., and Haining, F. (2024). The role of PI3k\/AKT signaling pathway in attenuating liver fibrosis: A comprehensive review. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1389329"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e1117","DOI":"10.1002\/cpz1.1117","article-title":"Concanavalin-A-Induced Acute Liver Injury in Mice","volume":"4","author":"Nabekura","year":"2024","journal-title":"Curr. Protoc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.21037\/atm-21-378","article-title":"Daidzein ameliorated concanavalin A-induced liver injury through the Akt\/GSK-3\u03b2\/Nrf2 pathway in mice","volume":"9","author":"Li","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Feng, Q., Yao, J., Zhou, G., Xia, W., Lyu, J., Li, X., Zhao, T., Zhang, G., Zhao, N., and Yang, J. (2018). Quantitative proteomic analysis reveals that arctigenin alleviates concanavalin A-induced hepatitis through suppressing immune system and regulating autophagy. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01881"},{"key":"ref_13","first-page":"5112","article-title":"Gossypin, a pentahydroxy glucosyl flavone, inhibits the transforming growth factor beta-activated kinase-1-mediated NF-\u03baB activation pathway, leading to potentiation of apoptosis, suppression of invasion, and abrogation of osteoclastogenesis","volume":"109","author":"Kunnumakkara","year":"2007","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/cbdd.14152","article-title":"Gossypin: A flavonoid with diverse pharmacological effects","volume":"101","author":"Song","year":"2023","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13007-024-01181-8","article-title":"A comprehensive tool in recycling plant-waste of Gossypium barbadense L agricultural and industrial waste extracts containing gossy pin and gossypol: Hepatoprotective, anti-inflammatory and antioxidant effects","volume":"20","author":"Mohammed","year":"2024","journal-title":"Plant Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/S0168-8278(01)00218-5","article-title":"Decreasing fibrogenesis: An immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B","volume":"35","author":"Kweon","year":"2001","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0168-8278(96)80008-0","article-title":"Liver stellate cells in chronic viral hepatitis: The effect of interferon therapy","volume":"24","author":"Guido","year":"1996","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1007\/s00428-002-0631-z","article-title":"Expression of SPARC by activated hepatic stellate cells and its correlation with the stages of fibrogenesis in human chronic hepatitis","volume":"441","author":"Nakatani","year":"2002","journal-title":"Virchows Arch."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1136\/gut.50.6.891","article-title":"Transcriptional regulation of hepatic stellate cell activation","volume":"50","author":"Mann","year":"2002","journal-title":"Gut"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41392-022-01257-8","article-title":"The sirtuin family in health and disease","volume":"7","author":"Wu","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8315","DOI":"10.7150\/thno.45922","article-title":"Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target","volume":"10","author":"Zhang","year":"2020","journal-title":"Theranostics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.freeradbiomed.2022.10.267","article-title":"NMN ameliorated radiation induced damage in NRF2-deficient cell and mice via regulating SIRT6 and SIRT7","volume":"193","author":"Zhao","year":"2022","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.taap.2018.01.009","article-title":"Pinocembrin from Penthorum chinense Pursh suppresses hepatic stellate cells activation through a unified SIRT3-TGF-\u03b2-Smad signaling pathway","volume":"341","author":"Zhou","year":"2018","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"108088","DOI":"10.1016\/j.intimp.2021.108088","article-title":"Anti-fibrotic activity of sitagliptin against concanavalin A-induced hepatic fibrosis. Role of Nrf2 activation\/NF-\u03baB inhibition","volume":"100","author":"Sharawy","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Cinar, I., Yayla, M., Toktay, E., and Binneto\u011flu, D. (2024). Effects of gossypin on acetaminophen-induced hepatotoxicity in mice. Trak. Univ. J. Nat. Sci., 25.","DOI":"10.23902\/trkjnat.1410800"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"117096","DOI":"10.1016\/j.lfs.2019.117096","article-title":"Mechanistic aspects of antifibrotic effects of honokiol in Con A-induced liver fibrosis in rats: Emphasis on TGF-\u03b2\/SMAD\/MAPK signaling pathways","volume":"240","author":"Elfeky","year":"2020","journal-title":"Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7147","DOI":"10.1080\/21655979.2022.2047403","article-title":"Trimetazidine inhibits liver fibrosis and hepatic stellate cell proliferation and blocks transforming growth factor-\u03b2 (TGF\u03b2)\/Smad signaling in vitro and in vivo","volume":"13","author":"Ding","year":"2022","journal-title":"Bioengineered"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.bcp.2015.09.001","article-title":"Antifibrotic mechanism of deferoxamine in concanavalin A induced-liver fibrosis: Impact on interferon therapy","volume":"98","author":"Darwish","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1007\/s43440-019-00055-4","article-title":"Mycophenolate mofetil attenuates concanavalin A-induced acute liver injury through modulation of TLR4\/NF-\u03baB and Nrf2\/HO-1 pathways","volume":"72","author":"Serrya","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"115223","DOI":"10.1016\/j.jep.2022.115223","article-title":"Cucurbitacin E glucoside alleviates concanavalin A-induced hepatitis through enhancing SIRT1\/Nrf2\/HO-1 and inhibiting NF-\u0138B\/NLRP3 signaling pathways","volume":"292","author":"Mohamed","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_31","first-page":"44","article-title":"Gossypin regulated doxorubicin-induced oxidative stress and inflammation in H9c2 cardiomyocyte cells","volume":"6","year":"2024","journal-title":"Med. Rec."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1002\/tox.23806","article-title":"Gossypin exert lipopolysaccharide induced lung inflammation via alteration of Nrf2\/HO-1 and NF-\u03baB signaling pathway","volume":"38","author":"Huang","year":"2023","journal-title":"Environ. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e3158","DOI":"10.1038\/cddis.2017.564","article-title":"SIRT3 protects hepatocytes from oxidative injury by enhancing ROS scavenging and mitochondrial integrity","volume":"8","author":"Liu","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4645","DOI":"10.1111\/bph.15215","article-title":"Small molecule-driven SIRT3-autophagy-mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes","volume":"177","author":"Zhang","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"108639","DOI":"10.1016\/j.pharmthera.2024.108639","article-title":"SIRT3: A potential therapeutic target for liver fibrosis","volume":"257","author":"Ning","year":"2024","journal-title":"Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5698931","DOI":"10.1155\/2016\/5698931","article-title":"Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox?","volume":"2016","author":"Biswas","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/hep.27332","article-title":"Hepatic inflammation and fibrosis: Functional links and key pathways","volume":"61","author":"Seki","year":"2015","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3898","DOI":"10.1039\/D0FO02736G","article-title":"Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K\/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD","volume":"12","author":"Li","year":"2021","journal-title":"Food Funct."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1053\/jhep.2003.50133","article-title":"Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis","volume":"37","author":"Abraldes","year":"2003","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.drup.2007.01.003","article-title":"Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy","volume":"10","author":"Maddika","year":"2007","journal-title":"Drug Resist. Updates"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s11596-015-1389-2","article-title":"Fenofibrate pre-treatment suppressed inflammation by activating phosphoinositide 3 kinase\/protein kinase B (PI3K\/Akt) signaling in renal ischemia-reperfusion injury","volume":"35","author":"Yang","year":"2015","journal-title":"J. Huazhong Univ. Sci. Technol. Med. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5385","DOI":"10.2147\/DDDT.S89096","article-title":"Ghrelin reduces liver impairment in a model of concanavalin A-induced acute hepatitis in mice","volume":"9","author":"Mao","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Zhao, W.-M., Li, X.-L., Zhu, Y., Shi, R., Wang, Z.-J., Xiao, J.-P., and Wang, D.-G. (2024). Diosmin ameliorates renal fibrosis through inhibition of inflammation by regulating SIRT3-mediated NF-\u03baB p65 nuclear translocation. BMC Complement. Med. Ther., 24.","DOI":"10.1186\/s12906-023-04330-z"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1007\/s12035-023-03743-8","article-title":"Gastrodin Regulates PI3K\/AKT-Sirt3 Signaling Pathway and Proinflammatory Mediators in Activated Microglia","volume":"61","author":"Zuo","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"116982","DOI":"10.1016\/j.lfs.2019.116982","article-title":"Pirfenidone alleviates concanavalin A-induced liver fibrosis in mice","volume":"239","author":"Salah","year":"2019","journal-title":"Life Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"117099","DOI":"10.1016\/j.taap.2024.117099","article-title":"Ferulic acid ameliorates concanavalin A-induced hepatic fibrosis in mice via suppressing TGF-\u03b2\/smad signaling","volume":"492","author":"Elazab","year":"2024","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s11626-999-0045-1","article-title":"Using Antibodies: A Laboratory Manual","volume":"35","author":"Shay","year":"1999","journal-title":"In Vitro Cell. Dev. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/18\/2\/74\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T10:14:39Z","timestamp":1770113679000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/18\/2\/74"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,2]]},"references-count":48,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["toxins18020074"],"URL":"https:\/\/doi.org\/10.3390\/toxins18020074","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,2]]}}}