{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T17:06:58Z","timestamp":1772557618398,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Etoricoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is widely prescribed for the management of inflammatory conditions. Despite its extensive clinical use, evidence regarding its hepatic safety profile remains limited and incompletely characterized. Aims: This study aimed to systematically evaluate the hepatic effects of etoricoxib in a murine model by integrating histopathological assessment with analysis of mRNA expression of key enzymes involved in arachidonic acid metabolism Methods: Male BALB\/c mice (n = 7 per group) received either low or high doses of etoricoxib (10.5 or 21 mg\/kg\/day) or celecoxib (35 or 70 mg\/kg\/day) for 28 consecutive days. Liver tissues were examined histologically using hematoxylin and eosin staining, while molecular alterations were assessed by quantitative PCR targeting representative cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) isoforms involved in arachidonic acid metabolism. Results: High-dose etoricoxib exposure was associated with pronounced hepatic histopathological alterations, including hepatocellular necrosis, inflammatory cell infiltration, and sinusoidal congestion. In contrast, low-dose treatment resulted in only mild vascular and cellular changes. At the molecular level, etoricoxib administration was associated with marked downregulation of several arachidonic acid\u2013metabolizing genes (including Cyp4a12 and Alox12), whereas Cox2 expression was significantly upregulated (p &lt; 0.05), indicating a shift toward a pro-inflammatory transcriptional profile. Conclusions: Etoricoxib exposure is associated with dose-dependent hepatic injury in mice, accompanied by coordinated transcriptional alterations in arachidonic acid\u2013metabolizing pathways. Notably, molecular changes were detectable even at low doses in the absence of overt histological damage, suggesting potential early indicators of hepatic stress. These findings underscore the importance of cautious dose optimization and further translational studies to clarify the long-term hepatic safety of etoricoxib in clinical settings.<\/jats:p>","DOI":"10.3390\/ph19030414","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T15:22:21Z","timestamp":1772551341000},"page":"414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatic Effects of Etoricoxib in Mice: Integrated Histopathological and Gene Expression Analysis"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4809-9743","authenticated-orcid":false,"given":"Yahya F.","family":"Jamous","sequence":"first","affiliation":[{"name":"Wellness and Preventive Medicine Institute, Health Sector, King Abdulaziz City for Science and Technology (KACST), Riyadh 11442, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Badrah S.","family":"Alghamdi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Neuroscience and Geroscience Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yazun","family":"Jarrar","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Al-Balqa Applied University, Al-Salt 19117, Jordan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5794-9976","authenticated-orcid":false,"given":"Emad A.","family":"Hindi","sequence":"additional","affiliation":[{"name":"Neuroscience and Geroscience Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Clinical Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah 22254, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2843-169X","authenticated-orcid":false,"given":"Mohammad Z.","family":"Alam","sequence":"additional","affiliation":[{"name":"Neuroscience and Geroscience Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jare.2017.11.004","article-title":"Arachidonic acid: Physiological roles and potential health benefits\u2014A review","volume":"11","author":"Tallima","year":"2018","journal-title":"J. Adv. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41392-020-00443-w","article-title":"Metabolism pathways of arachidonic acids: Mechanisms and potential therapeutic targets","volume":"6","author":"Wang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Khan, H., Xiao, J., and Cheang, W.S. (2021). Effects of Arachidonic Acid Metabolites on Cardiovascular Health and Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222112029"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Xia, Q., Gao, W., Yang, J., Xing, Z., and Ji, Z. (2024). The deregulation of arachidonic acid metabolism in ovarian cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1381894"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.prostaglandins.2019.02.003","article-title":"Effects of nonsteroidal anti-inflammatory drugs on the expression of arachidonic acid-metabolizing Cyp450 genes in mouse hearts, kidneys and livers","volume":"141","author":"Jarrar","year":"2019","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13293-016-0124-4","article-title":"Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl\/6 mice","volume":"8","author":"Grant","year":"2017","journal-title":"Biol. Sex Differ."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/j.2040-4603.2014.tb00548.x","article-title":"Energy metabolism in the liver","volume":"4","author":"Rui","year":"2014","journal-title":"Compr. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S1098-8823(03)00077-7","article-title":"Role of cytochrome P450-dependent arachidonic acid metabolites in liver physiology and pathophysiology","volume":"72","author":"Sacerdoti","year":"2003","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Alba, M.M., Ebright, B., Hua, B., Slarve, I., Zhou, Y., Jia, Y., Louie, S.G., and Stiles, B.L. (2023). Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1098467"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1515\/dmdi-2014-0001","article-title":"Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy","volume":"29","author":"Jarrar","year":"2014","journal-title":"Drug Metabol. Drug Interact."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1124\/dmd.117.078964","article-title":"Cytochrome P450 2J2: Potential role in drug metabolism and cardiotoxicity","volume":"46","author":"Solanki","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"ref_12","unstructured":"Ghlichloo, I., and Gerriets, V. (2023, May 01). Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK547742\/."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1007\/s12325-025-03153-3","article-title":"An Up-to-Date Description of the Use of Non-steroidal Anti-inflammatory Drugs (NSAIDs) in Italy: Evidence from Real Clinical Practice","volume":"42","author":"Perrone","year":"2025","journal-title":"Adv. Ther."},{"key":"ref_14","first-page":"45","article-title":"Etoricoxib for arthritis and pain management","volume":"2","author":"Brooks","year":"2006","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jamous, Y.F., Alghamdi, B.S., Jarrar, Y., Hindi, E.A., Alam, M.Z., Abd El-Aziz, G.S., Ibrahim, R.F., Bakhlgi, R., Algarni, S.M., and AboTaleb, H.A. (2024). Nephro- and Cardiotoxic Effects of Etoricoxib: Insights into Arachidonic Acid Metabolism and Beta-Adrenergic Receptor Expression in Experimental Mice. Pharmaceuticals, 17.","DOI":"10.3390\/ph17111454"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"598162","DOI":"10.1155\/2015\/598162","article-title":"The Effect of Etoricoxib on Hepatic Ischemia-Reperfusion Injury in Rats","volume":"2015","author":"Kunak","year":"2015","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1080\/14740338.2016.1225719","article-title":"Hepatotoxicity induced by coxibs: How concerned should we be?","volume":"15","author":"Bessone","year":"2016","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_18","first-page":"37","article-title":"Risk Factors for the Incidence of Overdose of Etoricoxib Drug in Outpatient at Hospital in Indonesia","volume":"1","author":"Nurmesa","year":"2024","journal-title":"Indones. J. Adm. Clin. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Albawa\u2019neh, A., Al Mansoori, M.G., Diab, S., Al Jasmi, F., and Akawi, N. (2022). Etoricoxib as a treatment of choice for patients with SLCO2A1 mutation exhibiting autosomal recessive primary hypertrophic osteoarthropathy: A case report. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.1053999"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1177\/0091270003257219","article-title":"Pharmacokinetics of etoricoxib in patients with hepatic impairment","volume":"43","author":"Agrawal","year":"2003","journal-title":"J. Clin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"103449","DOI":"10.1016\/j.etap.2020.103449","article-title":"The influence of five metallic nanoparticles on the expression of major drug-metabolizing enzyme genes with correlation of inflammation in mouse livers","volume":"80","author":"Jarrar","year":"2020","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e0802","DOI":"10.1097\/HC9.0000000000000802","article-title":"Arachidonic Acid Metabolism in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis","volume":"9","author":"Ma","year":"2025","journal-title":"Hepatol. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.12659\/MSM.900271","article-title":"Influence of CYP2C9 and COX-2 Genetic Polymorphisms on Clinical Efficacy of Non-Steroidal Anti-Inflammatory Drugs in Treatment of Ankylosing Spondylitis","volume":"23","author":"Wang","year":"2017","journal-title":"Med. Sci. Monit."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"364","DOI":"10.3904\/kjim.2010.25.4.364","article-title":"Increased expression of cyclooxygenase-2 is associated with the progression to cirrhosis","volume":"25","author":"Jeong","year":"2010","journal-title":"Korean J. Intern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"381","DOI":"10.2174\/1874467215666220413085316","article-title":"Upregulation of Beta 1 and Arachidonic Acid Metabolizing Enzymes in the Mouse Hearts and Kidneys after Sub Chronic Administration of Rofecoxib","volume":"16","author":"Askar","year":"2023","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Choi, J.H., and Thung, S.N. (2023). Advances in Histological and Molecular Classification of Hepatocellular Carcinoma. Biomedicines, 11.","DOI":"10.3390\/biomedicines11092582"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1111\/liv.14195","article-title":"Early ALT response to corticosteroid treatment distinguishes idiosyncratic drug-induced liver injury from autoimmune hepatitis","volume":"39","author":"Weber","year":"2019","journal-title":"Liver Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100737","DOI":"10.1016\/j.curtheres.2024.100737","article-title":"Biomarkers of Hepatic Toxicity: An Overview","volume":"100","author":"Thakur","year":"2024","journal-title":"Curr. Ther. Res. Clin. Exp."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"63","DOI":"10.2174\/0122115366268781231205103752","article-title":"Effects of Calamintha incana (Sm.) Helder Ethanolic Extract on the mRNA Expression of Drug-metabolizing cyp450s in the Mouse Livers","volume":"13","author":"Althaher","year":"2024","journal-title":"Microrna"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3937","DOI":"10.3748\/wjg.15.3937","article-title":"Celecoxib-induced cholestatic liver failure requiring orthotopic liver transplantation","volume":"15","author":"Malik","year":"2009","journal-title":"World J. Gastroenterol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1021\/acsptsci.8b00003","article-title":"Inhibition of Hepatotoxicity by a LXR Inverse Agonist in a Model of Alcoholic Liver Disease","volume":"1","author":"Sengupta","year":"2018","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2270188","DOI":"10.1080\/19932820.2023.2270188","article-title":"Effects of intermittent fasting on the histology and mRNA expression of major drug-metabolizing cyp450s in the liver of diabetic mice","volume":"18","author":"Jarrar","year":"2023","journal-title":"Libyan J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.etap.2018.05.021","article-title":"In vivo investigation on the chronic hepatotoxicity induced by sertraline","volume":"61","author":"Almansour","year":"2018","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_34","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":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/3\/414\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T15:35:28Z","timestamp":1772552128000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/3\/414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,3]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ph19030414"],"URL":"https:\/\/doi.org\/10.3390\/ph19030414","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,3]]}}}