{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:41:46Z","timestamp":1789015306042,"version":"build-2803163510"},"reference-count":56,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T00:00:00Z","timestamp":1647561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah","award":["G: 64-140-1441"],"award-info":[{"award-number":["G: 64-140-1441"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Liver fibrosis is a foremost medical concern worldwide. In Saudi Arabia, numerous risk factors contribute to its high rates. Lycorine\u2014a natural alkaloid\u2014has antioxidant, anti-inflammatory, and antitumor activates. It has been reported to inhibit STAT3 in cancer. Therefore, this study aimed at investigating the possible antifibrotic effect of lycorine against thioacetamide (TAA)-induced liver fibrosis in rats and at elucidating the possible mechanisms. Liver fibrosis was induced by TAA (200 mg\/kg i.p.), three per week for four weeks. Treatment with lycorine (0.5 and 1 mg\/kg\/d) amended TAA-induced rise of serum transaminases that was confirmed histopathologically. Moreover, it ameliorated liver fibrosis in a dose-dependent manner, as indicated by hindering the TAA-induced increase of hepatic hydroxyproline content, \u03b1-smooth muscle actin (\u03b1-SMA) and transforming growth factor (TGF-\u03b21) expressions. TAA-induced oxidative stress was amended by lycorine treatment via restoring reduced glutathione and diminishing lipid peroxidation. Moreover, lycorine ameliorated hepatic inflammation by preventing the rise of inflammatory cytokines. Notably, lycorine inhibited STAT3 activity, as evidenced by the decreased phospho-STAT3 expression, accompanied by the elevation of the hepatic Bax\/Bcl-2 ratio. In conclusion, lycorine hinders TAA-induced liver fibrosis in rats, due to\u2014at least partly\u2014its antioxidative and anti-inflammatory properties, along with its ability to inhibit STAT3 signaling.<\/jats:p>","DOI":"10.3390\/ph15030369","type":"journal-article","created":{"date-parts":[[2022,3,20]],"date-time":"2022-03-20T21:34:27Z","timestamp":1647812067000},"page":"369","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Lycorine Ameliorates Thioacetamide-Induced Hepatic Fibrosis in Rats: Emphasis on Antioxidant, Anti-Inflammatory, and STAT3 Inhibition Effects"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7824-8802","authenticated-orcid":false,"given":"Huda Mohammed","family":"Alkreathy","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1937-9300","authenticated-orcid":false,"given":"Ahmed","family":"Esmat","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,18]]},"reference":[{"key":"ref_1","unstructured":"Rouiller, C. (2013). The Liver: Morphology, Biochemistry, Physiology, Academic Press."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the world","volume":"70","author":"Asrani","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1159\/000374096","article-title":"Pathophysiology of Liver Fibrosis","volume":"33","author":"Pinzani","year":"2015","journal-title":"Dig. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/jhbp.245","article-title":"Recent advancement of molecular mechanisms of liver fibrosis","volume":"22","author":"Seki","year":"2015","journal-title":"J. Hepato-Biliary-Pancreat. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1755-1536-1-5","article-title":"Redox mechanisms in hepatic chronic wound healing and fibrogenesis","volume":"1","author":"Novo","year":"2008","journal-title":"Fibrogenes. Tissue Repair"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.1038\/sj.onc.1208469","article-title":"Stat3 regulates genes common to both wound healing and cancer","volume":"24","author":"Dauer","year":"2005","journal-title":"Oncogene"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nrm909","article-title":"STATs: Transcriptional control and biological impact","volume":"3","author":"Levy","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","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-\u03b21 production","volume":"25","author":"Ogata","year":"2006","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1038\/sj.onc.1203551","article-title":"Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors","volume":"19","author":"Hirano","year":"2000","journal-title":"Oncogene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"116","DOI":"10.4103\/0973-1296.96553","article-title":"Hepatoprotective and antioxidant activity of standardized herbal extracts","volume":"8","author":"Hiraganahalli","year":"2012","journal-title":"Pharmacogn. Mag."},{"key":"ref_12","first-page":"481","article-title":"Inhibitory effect of lycorine on cell division and cell elongation","volume":"14","author":"Dalessandro","year":"1973","journal-title":"Plant Cell Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.canlet.2008.08.029","article-title":"Lycorine induces apoptosis and down-regulation of Mcl-1 in human leukemia cells","volume":"274","author":"Liu","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.phytochem.2009.04.012","article-title":"Structure-activity studies on the lycorine pharmacophore: A potent inducer of apoptosis in human leukemia cells","volume":"70","author":"McNulty","year":"2009","journal-title":"Phytochemistry"},{"key":"ref_15","first-page":"26","article-title":"Antioxidant and Anticonvulsant Alkaloids in Crinum ornatum Bulb Extract","volume":"5","author":"Oleyede","year":"2010","journal-title":"World J. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.fitote.2011.09.008","article-title":"Evaluation of analgesic, anti-inflammatory and hepatoprotective effects of lycorine from Sternbergia fisheriana (Herbert) Rupr","volume":"83","author":"Acikara","year":"2012","journal-title":"Fitoterapia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"881","DOI":"10.3389\/fphar.2018.00881","article-title":"Lycorine Displays Potent Antitumor Efficacy in Colon Carcinoma by Targeting STAT3","volume":"9","author":"Wu","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"104884","DOI":"10.1016\/j.phrs.2020.104884","article-title":"Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis","volume":"158","author":"Liang","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1161\/CIRCULATIONAHA.119.042559","article-title":"Natural compound library screening identifies new molecules for the treatment of cardiac fibrosis and diastolic dysfunction","volume":"141","author":"Schimmel","year":"2020","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8528239","DOI":"10.1155\/2021\/8528239","article-title":"Dihydrolycorine Attenuates Cardiac Fibrosis and Dysfunction by Downregulating Runx1 following Myocardial Infarction","volume":"2021","author":"Ni","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5583","DOI":"10.1080\/21655979.2021.1967019","article-title":"Lycorine ameliorates isoproterenol-induced cardiac dysfunction mainly via inhibiting inflammation, fibrosis, oxidative stress and apoptosis","volume":"12","author":"Wu","year":"2021","journal-title":"Bioengineered"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1177\/0023677215573040","article-title":"Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats","volume":"49","author":"Wallace","year":"2015","journal-title":"Lab. Anim."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lam, P., Cheung, F., Tan, H.Y., Wang, N., Yuen, M.F., and Feng, Y. (2016). Hepatoprotective effects of chinese medicinal herbs: A focus on anti-inflammatory and anti-oxidative activities. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17040465"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.sjbs.2010.11.001","article-title":"Protection of human erythrocyte using Crinum asiaticum extract and lycorine from oxidative damage induced by 2-amidinopropane","volume":"18","author":"Ilavenil","year":"2011","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.intimp.2011.11.018","article-title":"Lycorine inhibits lipopolysaccharide-induced iNOS and COX-2 up-regulation in RAW264.7 cells through suppressing P38 and STATs activation and increases the survival rate of mice after LPS challenge","volume":"12","author":"Kang","year":"2012","journal-title":"Int. Immunopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1007\/s00204-015-1543-4","article-title":"Experimental models of liver fibrosis","volume":"90","author":"Cogliati","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.taap.2006.11.036","article-title":"Role of CYP2E1 and saturation kinetics in the bioactivation of thioacetamide: Effects of diet restriction and phenobarbital","volume":"219","author":"Chilakapati","year":"2007","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.taap.2007.11.010","article-title":"Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity","volume":"228","author":"Kang","year":"2008","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1021\/tx3002719","article-title":"Metabolism and toxicity of thioacetamide and thioacetamide S-Oxide in rat hepatocytes","volume":"25","author":"Hajovsky","year":"2012","journal-title":"Chem. Res. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1038\/ncomms3823","article-title":"Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology","volume":"4","author":"Mederacke","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E3297","DOI":"10.1073\/pnas.1400062111","article-title":"Origin of myofibroblasts in the fibrotic liver in mice","volume":"111","author":"Iwaisako","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","article-title":"Mechanisms of Hepatic Fibrogenesis","volume":"134","author":"Friedman","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_33","first-page":"122","article-title":"Molecular and tissue alterations of collagens in fibrosis","volume":"68\u201369","author":"Baffet","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1038\/s41598-020-57839-5","article-title":"Differential expression and localisation of TGF-\u03b2 isoforms and receptors in the murine epididymis","volume":"10","author":"Voisin","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/labinvest.3700669","article-title":"Pathobiology of transforming growth factor \u03b2 in cancer, fibrosis and immunologic disease, and therapeutic considerations","volume":"87","year":"2007","journal-title":"Lab. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chung, J.Y.F., Chan, M.K.K., Li, J.S.F., Chan, A.S.W., Tang, P.C.T., Leung, K.T., To, K.F., Lan, H.Y., and Tang, P.M.K. (2021). TGF-\u03b2 Signaling: From Tissue Fibrosis to Tumor Microenvironment. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147575"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.bbadis.2014.07.025","article-title":"Stat3 signaling activation crosslinking of TGF-\u03b21 in hepatic stellate cell exacerbates liver injury and fibrosis","volume":"1842","author":"Xu","year":"2014","journal-title":"Biochim. Biophys. Acta-Mol. Basis Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S2305-0500(15)30008-7","article-title":"Hepatoprotective mechanism of lycorine against carbon tetrachloride induced toxicity in swiss albino mice\u2014A proteomic approach Keywords: Lycorine CCl 4 Oxidative stress 2D gel MALDI-TOF-MS ATP synthase Regucalcin HSP 60","volume":"4","author":"Ilavenil","year":"2015","journal-title":"Asian Pac. J. Reprod."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Robert, S., Gicquel, T., Bodin, A., Lagente, V., and Boichot, E. (2016). Characterization of the MMP\/TIMP imbalance and collagen production induced by IL-1 \u03b2 or TNF-\u03b1 release from human hepatic stellate cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153118"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1248\/bpb.22.674","article-title":"Suppressive activity of lycoricidinol (narciclasine) against cytotoxicity of neutrophil-derived calprotectin, and its suppressive effect on rat adjuvant arthritis model","volume":"22","author":"Mikami","year":"1999","journal-title":"Biol. Pharm. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100224","DOI":"10.1016\/j.aohep.2020.06.010","article-title":"STAT3: A key regulator in liver fibrosis","volume":"21","author":"Zhao","year":"2021","journal-title":"Ann. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.bbrc.2019.03.156","article-title":"A novel STAT3 inhibitor, STX-0119, attenuates liver fibrosis by inactivating hepatic stellate cells in mice","volume":"513","author":"Choi","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","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":"Lopez","year":"2016","journal-title":"RSC Adv."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/cbdd.13160","article-title":"Cucurbitacin-B attenuates CCL4-induced hepatic fibrosis in mice through inhibition of STAT-3","volume":"91","author":"Sallam","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3595","DOI":"10.2147\/DDDT.S179876","article-title":"Asiatic acid ameliorates CCL4-induced liver fibrosis in rats: Involvement of Nrf2\/ARE, NF-\u03baB\/i\u03baB\u03b1, and JAK1\/STAT3 signaling pathways","volume":"12","author":"Fan","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_46","first-page":"1337","article-title":"S-allyl-cysteine attenuates carbon tetrachloride-induced liver fibrosis in rats by targeting STAT3\/SMAD3 pathway","volume":"10","author":"Gong","year":"2018","journal-title":"Am. J. Transl. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jfda.2018.09.008","article-title":"CCM111 prevents hepatic fibrosis via cooperative inhibition of TGF-\u03b2, Wnt and STAT3 signaling pathways","volume":"27","author":"Lin","year":"2019","journal-title":"J. Food Drug Anal."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.febslet.2004.10.095","article-title":"Effects of lycorine on HL-60 cells via arresting cell cycle and inducing apoptosis","volume":"578","author":"Liu","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/1475-2867-12-49","article-title":"Lycorine induces cell-cycle arrest in the G0\/G1 phase in K562 cells via HDAC inhibition","volume":"12","author":"Li","year":"2012","journal-title":"Cancer Cell Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"105816","DOI":"10.1016\/j.intimp.2019.105816","article-title":"Docosahexaenoic acid inhibits hepatic stellate cell activation to attenuate liver fibrosis in a PPAR\u03b3-dependent manner","volume":"75","author":"He","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4474","DOI":"10.1038\/s41467-021-24734-0","article-title":"CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells","volume":"12","author":"Koda","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Hubrecht, R.C., and Carter, E. (2019). The 3Rs and Humane Experimental Technique: Implementing Change. Animals, 9.","DOI":"10.3390\/ani9100754"},{"key":"ref_53","first-page":"344","article-title":"Effect of a short-term fast on ketamine-xylazine anesthesia in rats","volume":"50","author":"Struck","year":"2011","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_54","unstructured":"Bancroft, J.D., and Gamble, M. (2008). Theory and Practice of Histological Techniques, Elsevier Health Sciences. [6th ed.]."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Buchwalow, I.B., and B\u00f6cker, W. (2010). Immuno-Histochemistry Basics and Methods, Springer.","DOI":"10.1007\/978-3-642-04609-4"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1093\/clinchem\/34.3.497","article-title":"A simple method for clinical assay of superoxide dismutase","volume":"34","author":"Sun","year":"1988","journal-title":"Clin. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/3\/369\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:38:43Z","timestamp":1760135923000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/3\/369"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,18]]},"references-count":56,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ph15030369"],"URL":"https:\/\/doi.org\/10.3390\/ph15030369","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,18]]}}}