{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T01:39:27Z","timestamp":1793410767677,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1\/TLR-4\/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NF\u03baB p65 content resulting in decreased proinflammatory cytokines (TNF-\u03b1 and IL-1\u03b2). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt\/pS486-AMPK\/pS758-ULK1\/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2\/SOD cascade and inhibition of the HMGB1\/TLR-4\/RAGE \/MAPK p38\/NF\u03baB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK\/ULK1\/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis.<\/jats:p>","DOI":"10.3390\/toxics13070594","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T10:46:05Z","timestamp":1752662765000},"page":"594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4574-8411","authenticated-orcid":false,"given":"Engy A.","family":"Elsiad","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"},{"name":"Department of Clinical, Bio-in Molecules, Egyptian Drug Authority (EDA), Cairo 11553, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayat A.","family":"Abd El Aal","sequence":"additional","affiliation":[{"name":"Department of Clinical, Bio-in Molecules, Egyptian Drug Authority (EDA), Cairo 11553, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hesham A.","family":"Salem","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed F.","family":"El-Yamany","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9488-2320","authenticated-orcid":false,"given":"Mostafa A.","family":"Rabie","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1016\/j.phymed.2010.04.007","article-title":"Effect of combined administration of ginger (Zingiber officinale Roscoe) and atorvastatin on the liver of rats","volume":"17","author":"Heeba","year":"2010","journal-title":"Phytomedicine"},{"key":"ref_2","first-page":"37","article-title":"The Biochemical effects of Atorvastatin toxicity on the liver and muscles of adult albino rats","volume":"14","author":"Shehab","year":"2014","journal-title":"Egypt J. Forensic Sci. Appl. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1248\/bpb.b14-00505","article-title":"The glucagon-like peptide-1 analogue liraglutide inhibits oxidative stress and inflammatory response in the liver of rats with diet-induced non-alcoholic fatty liver disease","volume":"38","author":"Gao","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"110719","DOI":"10.1016\/j.fct.2019.110719","article-title":"Activation of pCREB\/Nrf-2 signaling mediates re-positioning of liraglutide as hepato-protective for methotrexate-induced liver injury (MILI)","volume":"132","author":"Abdelaziz","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Mm","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_6","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\u2212 \u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.aohep.2019.04.011","article-title":"The GLP-1 analog liraglutide attenuates acute liver injury in mice","volume":"18","author":"Milani","year":"2019","journal-title":"Ann. Hepatol."},{"key":"ref_8","first-page":"6165","article-title":"Atorvastatin induces hepatotoxicity in diabetic rats via oxidative stress, inflammation, and anti-apoptotic pathway","volume":"25","author":"Zeng","year":"2019","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"ref_9","unstructured":"Ponroy, N. (2014). Statins Inhibit Cytomegalovirus Replication by Interfering with the Isoprenoid Arm of the Mevalonate Pathway, University of Zurich."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1503\/cmaj.1041403","article-title":"Effectiveness of statins for secondary prevention in elderly patients after acute myocardial infarction: An evaluation of class effect","volume":"172","author":"Zhou","year":"2005","journal-title":"CMAJ"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1007\/s11883-003-0008-z","article-title":"Isoprenoid metabolism and the pleiotropic effects of statins","volume":"5","author":"Laufs","year":"2003","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1159\/000046889","article-title":"Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of Parkinson\u2019s disease","volume":"10","author":"Ebadi","year":"2001","journal-title":"Neurosignals"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1152\/physrev.00044.2005","article-title":"The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology","volume":"87","author":"Bedard","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1007\/s00204-014-1338-z","article-title":"Antioxidative defense mechanisms controlled by Nrf2: State-of-the-art and clinical perspectives in neurodegenerative diseases","volume":"88","author":"Lim","year":"2014","journal-title":"Arch. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1002\/jat.3825","article-title":"Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway","volume":"39","author":"Li","year":"2019","journal-title":"J. Appl. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chatterjee, S. (2016). Oxidative stress, inflammation, and disease. Oxidative Stress and Biomaterials, Elsevier.","DOI":"10.1016\/B978-0-12-803269-5.00002-4"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1600-065X.2007.00574.x","article-title":"High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity","volume":"220","author":"Bianchi","year":"2007","journal-title":"Immunol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1517\/14728222.2011.575360","article-title":"HMGB1, TLR and RAGE: A functional tripod that leads to diabetic inflammation","volume":"15","author":"Volpe","year":"2011","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"767","DOI":"10.4049\/jimmunol.1900860","article-title":"Interplay between RAGE and TLR4 regulates HMGB1-induced inflammation by promoting cell surface expression of RAGE and TLR4","volume":"205","author":"Zhong","year":"2020","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1517\/14728220902794939","article-title":"Toll like receptors in liver ischemia reperfusion injury: A novel target for therapeutic modulation?","volume":"13","author":"Katsargyris","year":"2009","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.transproceed.2011.11.001","article-title":"The role of CD14 and Toll-like receptor 4 of Kupffer cells in hepatic ischemia-reperfusion injury in rats","volume":"44","author":"Luan","year":"2012","journal-title":"Proc. Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1172\/JCI26252","article-title":"Caspases: Pharmacological manipulation of cell death","volume":"115","author":"Lavrik","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"C1208","DOI":"10.1152\/ajpcell.00226.2006","article-title":"Statin-induced apoptosis and skeletal myopathy","volume":"291","author":"Dirks","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Oh, Y.S., and Jun, H.-S. (2017). Effects of glucagon-like peptide-1 on oxidative stress and Nrf2 signaling. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010026"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4872","DOI":"10.7150\/thno.86831","article-title":"Targeting redox imbalance in neurodegeneration: Characterizing the role of GLP-1 receptor agonists","volume":"13","author":"Ghosh","year":"2023","journal-title":"Theranostics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8974960","DOI":"10.1155\/2023\/8974960","article-title":"Liraglutide Attenuates Hepatic Oxidative Stress, Inflammation, and Apoptosis in Streptozotocin-Induced Diabetic Mice by Modulating the Wnt\/\u03b2-Catenin Signaling Pathway","volume":"2023","author":"Yu","year":"2023","journal-title":"Mediat. Inflamm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.bbrc.2019.04.160","article-title":"Protective effect of the glucagon-like peptide-1 analogue liraglutide on carbon tetrachloride-induced acute liver injury in mice","volume":"514","author":"Zhang","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.drudis.2016.01.013","article-title":"The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson\u2019s disease: Mechanisms of action","volume":"21","author":"Athauda","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"108995","DOI":"10.1016\/j.intimp.2022.108995","article-title":"GLP-1 mediates the neuroprotective action of crocin against cigarette smoking-induced cognitive disorders via suppressing HMGB1-RAGE\/TLR4-NF-\u03baB pathway","volume":"110","author":"Anis","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"105867","DOI":"10.1016\/j.phrs.2021.105867","article-title":"Liraglutide protects against lethal renal ischemia-reperfusion injury by inhibiting high-mobility group box 1 nuclear-cytoplasmic translocation and release","volume":"173","author":"Li","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1074\/jbc.M109.067207","article-title":"GLP-1 mediates antiapoptotic effect by phosphorylating Bad through a \u03b2-arrestin 1-mediated ERK1\/2 activation in pancreatic \u03b2-cells","volume":"285","author":"Quoyer","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1042\/BJ20120546","article-title":"AMP-activated protein kinase: New regulation, new roles?","volume":"445","author":"Carling","year":"2012","journal-title":"Biochem. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"147","DOI":"10.3892\/mmr.2020.11786","article-title":"Liraglutide protects palmitate-induced INS-1 cell injury by enhancing autophagy mediated via FoxO1","volume":"23","author":"Li","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1042\/EBC20170027","article-title":"mTORC1 as the main gateway to autophagy","volume":"61","author":"Otten","year":"2017","journal-title":"Essays Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/nrm2249","article-title":"AMP-activated\/SNF1 protein kinases: Conserved guardians of cellular energy","volume":"8","author":"Hardie","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"575","DOI":"10.2147\/DMSO.S447182","article-title":"Liraglutide improves nonalcoholic fatty liver disease in diabetic mice by activating autophagy through AMPK\/mTOR signaling pathway","volume":"17","author":"Liao","year":"2024","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1042\/BJ20090613","article-title":"AMPK\u03b11 regulates the antioxidant status of vascular endothelial cells","volume":"421","author":"Colombo","year":"2009","journal-title":"Biochem. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"H2123","DOI":"10.1152\/ajpheart.00707.2010","article-title":"Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury","volume":"300","author":"Paiva","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1111\/bph.12648","article-title":"Resveratrol decreases fructose-induced oxidative stress, mediated by NADPH oxidase via an AMPK-dependent mechanism","volume":"171","author":"Cheng","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/jgh.16752","article-title":"Influence of glucagon-like peptide-1 receptor agonists on hepatic events in type 2 diabetes: A systematic review and meta-analysis","volume":"40","author":"Passos","year":"2025","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.1111\/j.1755-5922.2010.00256.x","article-title":"The cardiovascular effects of GLP-1 receptor agonists","volume":"30","author":"Okerson","year":"2012","journal-title":"Cardiovasc. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.jhep.2010.09.032","article-title":"Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase","volume":"54","author":"Zvibel","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13098-025-01635-6","article-title":"Safety, efficacy, and cardiovascular benefits of combination therapy with SGLT-2 inhibitors and GLP-1 receptor agonists in patients with diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials","volume":"17","author":"Mousavi","year":"2025","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1177\/1074248419838511","article-title":"SGLT-2 inhibitors and GLP-1 agonists: First-line therapy for diabetes with established cardiovascular disease","volume":"24","author":"Sajja","year":"2019","journal-title":"J. Cardiovasc. Pharmacol. Ther."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/7\/594\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:10:32Z","timestamp":1760033432000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/7\/594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,16]]},"references-count":45,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["toxics13070594"],"URL":"https:\/\/doi.org\/10.3390\/toxics13070594","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,16]]}}}