{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:27:12Z","timestamp":1785414432593,"version":"3.56.0"},"reference-count":93,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Imam Mohammad ibn Saud Islamic University","award":["IMSIU-DDRSP2601"],"award-info":[{"award-number":["IMSIU-DDRSP2601"]}]},{"award":["IMSIU-DDRSP2601"],"award-info":[{"award-number":["IMSIU-DDRSP2601"]}],"id":[{"id":"https:\/\/ror.org\/05gxjyb39","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Introduction: Oxidative stress and inflammation are major factors linked to obesity and metabolic dysfunction, leading to a significantly higher risk of related diseases. Atorvastatin and liraglutide possess lipid-lowering, antioxidant, and anti-inflammatory effects that could synergistically improve obesity-related perturbations through modulation of the Nrf2\/HO-1 signaling pathway. Methodology: We assessed liraglutide\u2019s pharmacological potential in extending atorvastatin\u2019s benefit on obesity, hyperlipidemia, and fatty liver in rats fed a high-fat diet (HFD) for 12 weeks. We specifically evaluated the effects of liraglutide treatment on atorvastatin-induced anti-inflammatory and antioxidant mechanisms, with a particular focus on Nrf2\/HO 1 modulation in adipose and hepatic tissue. In silico analyses, including molecular docking and AlphaFold- Multimer modeling, evaluated the binding affinities of atorvastatin and liraglutide to Nrf2 and HO 1. Results: Compared to ND, the HFD-fed rats had a significantly higher final body weight (362.4 \u00b1 12.7 g vs. 245.6 \u00b1 9.8 g in ND, p &lt; 0.05). There was a marked increase in serum total cholesterol (178.6 \u00b1 9.2 mg\/dL vs. 98.3 \u00b1 6.4), fasting glucose (340.1 \u00b1 8.2 mg\/dL vs. 82.3 \u00b1 3.1), HbA1c (7.8 \u00b1 0.3 vs. 4.5 \u00b1 0.2), and hepatic COX-2 expression (99.9 \u00b1 6.3 vs 19.6 \u00b1 2.4). The oxidative stress markers were also disturbed, as indicated by SOD (42.5 \u00b1 3.1 vs. 95.2 \u00b1 4.6 U\/mg protein), GSH (18.3 \u00b1 1.5 vs. 42.7 \u00b1 2.8 nmol\/mg), and p62 (0.005 \u00b1 0.001 vs. 0.125 \u00b1 0.01). Atorvastatin lowered cholesterol (121.2 \u00b1 7.5 mg\/dL), COX-2 (61.3 \u00b1 3.3), and body weight (301.7 \u00b1 11.5 g) compared to HFD. Meanwhile, liraglutide caused a greater reduction in body weight (268.5 \u00b1 10.3 g), glucose (112.5 \u00b1 6.7 mg\/dL), and COX-2 (42.2 \u00b1 2.9) than atorvastatin. The combination therapy produced the most significant effects, returning body weight (253.6 \u00b1 9.1 g) to baseline, normalizing glucose and lipids, reducing COX-2 to 22.9 \u00b1 2.0, and reactivating the Nrf2\/HO-1 pathway, as shown by increased HO-1 expression and the restoration of p62 levels (0.078 \u00b1 0.004). In silico analyses suggest that atorvastatin favorably binds to Nrf2 and HO-1, while liraglutide interacts with structurally relevant interfaces on these proteins, providing a mechanistic basis for their complementary antioxidant and cytoprotective effects. Conclusions: Our findings support targeting the Nrf2\/HO-1 signaling pathway as a potential therapy for reversing hyperlipidemia and preventing mediators of inflammation and oxidative stress damage in the liver tissue. The evidence of increased efficacy observed with the combined atorvastatin and liraglutide supports a potential novel understanding of the complementary effects of atorvastatin and liraglutide. This finding requires further investigation to elucidate the combination\u2019s therapeutic advantages in treating metabolic disorder scenarios.<\/jats:p>","DOI":"10.3390\/pharmaceutics18040490","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:35:42Z","timestamp":1776339342000},"page":"490","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Effect of Liraglutide on the Hypolipidemic, Anti-Inflammatory, and Antioxidant Properties of Atorvastatin Mediated via the Nrf2\/HO-1 Signaling Pathway: In Vivo and In Silico Validation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3682-869X","authenticated-orcid":false,"given":"Sherif A.","family":"Kamar","sequence":"first","affiliation":[{"name":"Department of Basic Medical Science, Faculty of Dentistry, Al-Ahliyya Amman University, Amman P.O. Box 19111, Jordan"},{"name":"Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1226-3057","authenticated-orcid":false,"given":"Yosra M.","family":"Magdy","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4326-3663","authenticated-orcid":false,"given":"Tamer M. M.","family":"Abuamara","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Science, Faculty of Dentistry, Al-Ahliyya Amman University, Amman P.O. Box 19111, Jordan"},{"name":"Department of Histology, Faculty of Medicine, Al-Azhar University, Cairo 11651, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amina A.","family":"Sedky","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahani Mohamed Ibrahim","family":"Al-Hazani","sequence":"additional","affiliation":[{"name":"Biology Department, College of Science and Humanities, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"Alhelf","sequence":"additional","affiliation":[{"name":"Biotechnology School, Nile University, Giza 12677, Egypt"},{"name":"Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 12613, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9941-2402","authenticated-orcid":false,"given":"Eman Serry","family":"Zayed","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Faculty of Medicine, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3039-7646","authenticated-orcid":false,"given":"Tarek A.","family":"A. Yousef","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3193-7328","authenticated-orcid":false,"given":"Abdullah","family":"Al-Dakhil","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2224-8165","authenticated-orcid":false,"given":"Mortaga M.","family":"Abou-Krisha","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samah J.","family":"Almehmadi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Khedr","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.cmet.2023.02.003","article-title":"The Global Burden of Metabolic Disease: Data from 2000 to 2019","volume":"35","author":"Chew","year":"2023","journal-title":"Cell Metab."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chen, R., Safiri, S., Behzadifar, M., Kong, J.D., Zguira, M.S., Bragazzi, N.L., Zhong, W., and Zhang, W. (2022). Health Effects of Metabolic Risks in the United States from 1990 to 2019. Front. Public Health, 10.","DOI":"10.3389\/fpubh.2022.751126"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mohamed, D., Ezzat, S., Elayat, W., El-Kharashi, O., El-Kareem, H., Nahas, H., Abdel-Wahab, B., Alshawwa, S., Saleh, A., and Helmy, Y. (2022). Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study. Pharmaceuticals, 15.","DOI":"10.3390\/ph15070832"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1186\/s10020-024-01019-y","article-title":"The Interplay of Factors in Metabolic Syndrome: Understanding Its Roots and Complexity","volume":"30","author":"Islam","year":"2024","journal-title":"Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s43044-023-00352-7","article-title":"Prospects of Potential Adipokines as Therapeutic Agents in Obesity-Linked Atherogenic Dyslipidemia and Insulin Resistance","volume":"75","author":"Roy","year":"2023","journal-title":"Egypt. Heart J."},{"key":"ref_6","first-page":"1","article-title":"Metabolic Risk Factors in Obesity and Diabetes Mellitus: Implications in the Pathogenesis and Therapy","volume":"3","author":"Banerjee","year":"2017","journal-title":"Integr Obes. Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3390\/ijms16010378","article-title":"Oxidative Stress in Obesity: A Critical Component in Human Diseases","volume":"16","author":"Marseglia","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_8","first-page":"192","article-title":"Adipose Tissue as an Endocrine Organ: From Theory to Practice","volume":"83","author":"Takada","year":"2007","journal-title":"J. Pediatr. (Rio J.)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1007\/s00424-006-0055-8","article-title":"Acute and Prolonged Effects of TNF-\u03b1 on the Expression and Secretion of Inflammation-Related Adipokines by Human Adipocytes Differentiated in Culture","volume":"452","author":"Wang","year":"2006","journal-title":"Pfl\u00fcg. Arch."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s13105-024-01048-5","article-title":"Increased Expression of IL-1\u03b2 in Adipose Tissue in Obesity Influences the Development of Colon Cancer by Promoting Inflammation","volume":"81","author":"Neira","year":"2025","journal-title":"J. Physiol. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Martemucci, G., Fracchiolla, G., Muraglia, M., Tardugno, R., Dibenedetto, R.S., and D\u2019Alessandro, A.G. (2023). Metabolic Syndrome: A Narrative Review from the Oxidative Stress to the Management of Related Diseases. Antioxidants, 12.","DOI":"10.3390\/antiox12122091"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tauil, R.B., Golono, P.T., de Lima, E.P., de Alvares Goulart, R., Guiguer, E.L., Bechara, M.D., Nicolau, C.C.T., Yanaguizawa Junior, J.L., Fiorini, A.M.R., and M\u00e9ndez-S\u00e1nchez, N. (2024). Metabolic-Associated Fatty Liver Disease: The Influence of Oxidative Stress, Inflammation, Mitochondrial Dysfunctions, and the Role of Polyphenols. Pharmaceuticals, 17.","DOI":"10.3390\/ph17101354"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Park, J.S., Rustamov, N., and Roh, Y.S. (2023). The Roles of NFR2-Regulated Oxidative Stress and Mitochondrial Quality Control in Chronic Liver Diseases. Antioxidants, 12.","DOI":"10.3390\/antiox12111928"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Allameh, A., Niayesh-mehr, R., Aliarab, A., Sebastiani, G., and Pantopoulos, K. (2023). Oxidative Stress in Liver Pathophysiology and Disease. Antioxidants, 12.","DOI":"10.3390\/antiox12091653"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1007\/s00018-016-2223-0","article-title":"Role of Nrf2\/HO-1 System in Development, Oxidative Stress Response and Diseases: An Evolutionarily Conserved Mechanism","volume":"73","author":"Loboda","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6909","DOI":"10.3748\/wjg.v28.i48.6909","article-title":"Nuclear Factor Erythroid 2-Related Factor 2-Mediated Signaling and Metabolic Associated Fatty Liver Disease","volume":"28","author":"Bukke","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hasan, S.K., Jayakumar, S., Espina Barroso, E., Jha, A., Catalano, G., Sandur, S.K., and Noguera, N.I. (2025). Molecular Targets of Oxidative Stress: Focus on Nuclear Factor Erythroid 2\u2013Related Factor 2 Function in Leukemia and Other Cancers. Cells, 14.","DOI":"10.3390\/cells14100713"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"102389","DOI":"10.1016\/j.redox.2022.102389","article-title":"Signal Amplification in the KEAP1-NRF2-ARE Antioxidant Response Pathway","volume":"54","author":"Liu","year":"2022","journal-title":"Redox Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Saha, S., Buttari, B., Panieri, E., Profumo, E., and Saso, L. (2020). An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation. Molecules, 25.","DOI":"10.3390\/molecules25225474"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Xia, Y., Zhai, X., Qiu, Y., Lu, X., and Jiao, Y. (2022). The Nrf2 in Obesity: A Friend or Foe?. Antioxidants, 11.","DOI":"10.3390\/antiox11102067"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8061","DOI":"10.2147\/JIR.S490418","article-title":"The NRF-2\/HO-1 Signaling Pathway: A Promising Therapeutic Target for Metabolic Dysfunction-Associated Steatotic Liver Disease","volume":"17","author":"Li","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3214196","DOI":"10.1155\/2019\/3214196","article-title":"New Insights into the Nrf-2\/HO-1 Signaling Axis and Its Application in Pediatric Respiratory Diseases","volume":"2019","author":"Zhang","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.aohep.2019.11.010","article-title":"NRF-2 and Nonalcoholic Fatty Liver Disease","volume":"19","year":"2020","journal-title":"Ann. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wang, L., and He, C. (2022). Nrf2-Mediated Anti-Inflammatory Polarization of Macrophages as Therapeutic Targets for Osteoarthritis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.967193"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Galicia-moreno, M., Lucano-landeros, S., Monroy-ramirez, H.C., Silva-gomez, J., Gutierrez-cuevas, J., Santos, A., and Armendariz-borunda, J. (2020). Roles of NRF2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects. Antioxidants, 9.","DOI":"10.3390\/antiox9100980"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"597134","DOI":"10.1155\/2015\/597134","article-title":"The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism","volume":"2015","author":"Chambel","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.freeradbiomed.2022.06.226","article-title":"Nonalcoholic Steatohepatitis and Mechanisms by Which It Is Ameliorated by Activation of the CNC-bZIP Transcription Factor Nrf2","volume":"188","author":"Bathish","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7188","DOI":"10.1128\/MCB.00915-07","article-title":"NRF2 Modulates Aryl Hydrocarbon Receptor Signaling: Influence on Adipogenesis","volume":"27","author":"Shin","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1002\/oby.20929","article-title":"Deficiency in Nrf2 Transcription Factor Decreases Adipose Tissue Mass and Hepatic Lipid Accumulation in Leptin-Deficient Mice","volume":"23","author":"Xu","year":"2015","journal-title":"Obesity"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1089\/ars.2017.7342","article-title":"Transcriptional Regulation by Nrf2","volume":"29","author":"Tonelli","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/s42003-024-06243-0","article-title":"Activation of Nrf2\/HO-1 Signaling Pathway Exacerbates Cholestatic Liver Injury","volume":"7","author":"Wang","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.bbamcr.2018.02.010","article-title":"Nrf2-Keap1 Signaling in Oxidative and Reductive Stress","volume":"1865","author":"Bellezza","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_33","first-page":"328","article-title":"HMG-CoA Reductase Inhibitors (Statins) and Their Drug Interactions Involving CYP Enzymes, P-Glycoprotein and OATP Transporters-An Overview","volume":"22","author":"Balasubramanian","year":"2021","journal-title":"Curr. Drug Metab."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Khatiwada, N., and Hong, Z. (2024). Potential Benefits and Risks Associated with the Use of Statins. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16020214"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.5114\/aoms\/141155","article-title":"Statins as Anti-Pyroptotic Agents","volume":"17","author":"Khalifeh","year":"2021","journal-title":"Arch. Med. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nrgastro.2010.213","article-title":"NF-\u03baB in the Liver-Linking Injury, Fibrosis and Hepatocellular Carcinoma","volume":"8","author":"Luedde","year":"2011","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Mansouri, A., Reiner, \u017d., Ruscica, M., Tedeschi-Reiner, E., Radbakhsh, S., Ekta, M.B., and Sahebkar, A. (2022). Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2\/HO-1 Signaling in Different Diseases. J. Clin. Med., 11.","DOI":"10.3390\/jcm11051313"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Jaikumkao, K., Pongchaidecha, A., Thongnak, L.O., Wanchai, K., Arjinajarn, P., Chatsudthipong, V., Chattipakorn, N., and Lungkaphin, A. (2016). Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0164528"},{"key":"ref_39","first-page":"33","article-title":"The Combination of Atorvastatin With Silymarin Enhances Hypolipidemic, Antioxidant and Anti-Inflammatory Effects in a Rat Model of Metabolic Syndrome","volume":"70","author":"Oliyarnyk","year":"2021","journal-title":"Physiol. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1007\/s12640-016-9693-6","article-title":"Coenzyme Q10 Prevents Mitochondrial Dysfunction and Facilitates Pharmacological Activity of Atorvastatin in 6-OHDA Induced Dopaminergic Toxicity in Rats","volume":"31","author":"Prajapati","year":"2017","journal-title":"Neurotox. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e3310","DOI":"10.1002\/dmrr.3310","article-title":"Statins Are Associated with New Onset Type 2 Diabetes Mellitus (T2DM) in Medicare Patients \u226565 Years","volume":"36","author":"Tangelloju","year":"2020","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Al Qassab, M., Mneimneh, M., Jradi, A., Derbas, B., Dabboussi, D., Khoury Baini, J., Katrib, N., Chaarani, N., Attieh, P., and Kanaan, A. (2025). The Expanding Role of GLP-1 Receptor Agonists: Advancing Clinical Outcomes in Metabolic and Mental Health. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47040285"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13098-025-01623-w","article-title":"GLP-1-Based Therapies for Type 2 Diabetes: From Single, Dual and Triple Agonists to Endogenous GLP-1 Production and L-Cell Differentiation","volume":"17","author":"Movahednasab","year":"2025","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Piccirillo, F., Mastroberardino, S., Nusca, A., Frau, L., Guarino, L., Napoli, N., Ussia, G.P., and Grigioni, F. (2023). Novel Antidiabetic Agents and Their Effects on Lipid Profile: A Single Shot for Several Cardiovascular Targets. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210164"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.bbrc.2020.03.032","article-title":"Liraglutide Ameliorates Obesity-Related Nonalcoholic Fatty Liver Disease by Regulating Sestrin2-Mediated Nrf2\/HO-1 Pathway","volume":"525","author":"Han","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"119523","DOI":"10.1016\/j.lfs.2021.119523","article-title":"Reduction in TNF Alpha and Oxidative Stress by Liraglutide: Impact on Ketamine-Induced Cognitive Dysfunction and Hyperlocomotion in Rats","volume":"278","author":"Sedky","year":"2021","journal-title":"Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1111\/fcp.12765","article-title":"The Vascular Impact of Dapagliflozin, Liraglutide, and Atorvastatin Alone or in Combinations in Type 2 Diabetic Rat Model","volume":"36","author":"Hammadi","year":"2022","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.jtcme.2017.06.004","article-title":"Dillenia indica L. Attenuates Diabetic Nephropathy via Inhibition of Advanced Glycation End Products Accumulation in STZ-Nicotinamide Induced Diabetic Rats","volume":"8","author":"Kaur","year":"2018","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1507\/endocrj1954.27.411","article-title":"Clinical Evaluation of Measuring Glycosylated Hemoglobin Levels for Assessing the Long-Term Blood Glucose Control in Diabetics","volume":"27","author":"Inada","year":"1980","journal-title":"Endocrinol. Jpn."},{"key":"ref_50","first-page":"244","article-title":"Evaluation of Glutathione Peroxidase in the Blood and Tumor Tissue of Oral Squamous Cell Carcinoma Patients","volume":"21","author":"Deshpande","year":"2023","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_51","first-page":"146","article-title":"Alteration of Autophagy Gene Expression by Different Intensity of Exercise in Gastrocnemius and Soleus Muscles of Wistar Rats","volume":"18","author":"Tarawan","year":"2019","journal-title":"J. Sports Sci. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.toxrep.2021.01.001","article-title":"Hepatoprotective, Antioxidant and, Anti-Inflammatory Potentials of Gallic Acid in Carbon Tetrachloride-Induced Hepatic Damage in Wistar Rats","volume":"8","author":"Ojeaburu","year":"2021","journal-title":"Toxicol. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: An Advanced Semantic Chemical Editor, Visualization, and Analysis Platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminform."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1016\/S0040-4039(01)94977-9","article-title":"A New Model for Calculating Atomic Charges in Molecules","volume":"19","author":"Gasteiger","year":"1978","journal-title":"Tetrahedron Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B","article-title":"Automated Docking Using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function","volume":"19","author":"Morris","year":"1998","journal-title":"J. Comput. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/s41596-024-01060-5","article-title":"Easy and Accurate Protein Structure Prediction Using ColabFold","volume":"20","author":"Kim","year":"2025","journal-title":"Nat. Protoc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e4792","DOI":"10.1002\/pro.4792","article-title":"UCSF ChimeraX: Tools for Structure Building and Analysis","volume":"32","author":"Meng","year":"2023","journal-title":"Protein Sci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Alyousef, A.M., Mekawy, D.Z., Bashumeel, Y.Y., Mohamed, S.M., Almigbal, T.H., Batais, M.A., and Alrasheed, A.A. (2025). The Prevalence of Metabolic Syndrome in Patients with Non-Alcoholic Fatty Liver Disease in Primary Care Clinics at King Saud University Medical City, Riyadh, Saudi Arabia. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1551201"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"10124","DOI":"10.1038\/s41598-025-91482-2","article-title":"Prevalence of Metabolic Dysfunction-Associated Fatty Liver Disease among Information Technology Employees in India","volume":"15","author":"Bhargava","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_60","first-page":"884","article-title":"Non-Alcoholic Fatty Liver Disease, Metabolic Syndrome, and Type 2 Diabetes Mellitus: Where Do We Stand Today?","volume":"19","author":"Mitrovic","year":"2023","journal-title":"Arch. Med. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Mohamed, D.I., Abo Nahas, H.H., Elshaer, A.M., El-Waseef, D.A., El-Kharashi, O.A., Mohamed, S.M., Sabry, Y.G., Almaimani, R.A., Almasmoum, H.A., and Altamimi, A.S. (2023). Unveiling the Interplay between NSAID-Induced Dysbiosis and Autoimmune Liver Disease in Children: Insights into the Hidden Gateway to Autism Spectrum Disorders. Evidence from Ex Vivo, in Vivo, and Clinical Studies. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1268126"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e320","DOI":"10.1016\/j.jacl.2024.04.001","article-title":"Obesity, Dyslipidemia, and Cardiovascular Disease: A Joint Expert Review from the Obesity Medicine Association and the National Lipid Association 2024","volume":"18","author":"Bays","year":"2024","journal-title":"J. Clin. Lipidol."},{"key":"ref_63","first-page":"e65202","article-title":"Lipid-Lowering Medications for Managing Dyslipidemia: A Narrative Review","volume":"16","author":"Alqahtani","year":"2024","journal-title":"Cureus"},{"key":"ref_64","first-page":"639","article-title":"Therapeutic Strategies Targeting Oxidative Stress to Improve Dyslipidemia and Left Ventricular Hypertrophy","volume":"36","author":"Reis","year":"2017","journal-title":"Cardiol. Port. J. Cardiol. Off. J. Port. Soc. Cardiol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Mohamed, D., El-Waseef, D.A.E.-D.A., Nabih, E., El-Kharashi, O., El-Kareem, H.A., Nahas, H.A., Abdel-Wahab, B., Helmy, Y., Alshawwa, S., and Saied, E. (2022). Acetylsalicylic Acid Suppresses Alcoholism-Induced Cognitive Impairment Associated with Atorvastatin Intake by Targeting Cerebral miRNA155 and NLRP3: In Vivo, and In Silico Study. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14030529"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Spoiala, E.L., Cinteza, E., Vatasescu, R., Vlaiculescu, M.V., and Moisa, S.M. (2024). Statins\u2014Beyond Their Use in Hypercholesterolemia: Focus on the Pediatric Population. Children, 11.","DOI":"10.3390\/children11010117"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s12016-020-08791-9","article-title":"Anti-Inflammatory Action of Statins in Cardiovascular Disease: The Role of Inflammasome and Toll-Like Receptor Pathways","volume":"60","author":"Koushki","year":"2021","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.metabol.2016.04.004","article-title":"Pharmacological Management of Nonalcoholic Fatty Liver Disease","volume":"65","author":"Barb","year":"2016","journal-title":"Metab.-Clin. Exp."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0022-2275(20)34205-X","article-title":"Atorvastatin Action Involves Diminished Recovery of Hepatic HBG-CoA Reductase Activity","volume":"39","author":"Ness","year":"1998","journal-title":"J. Lipid Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"174906","DOI":"10.1016\/j.ejphar.2022.174906","article-title":"Molecular Targets of Statins and Their Potential Side Effects: Not All the Glitter Is Gold","volume":"922","author":"Patel","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1161\/ATVBAHA.121.316159","article-title":"Statins Are Associated With Increased Insulin Resistance and Secretion","volume":"41","author":"Abbasi","year":"2021","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1038\/s41598-022-05323-7","article-title":"Liraglutide, a Glucagon-like Peptide 1 Receptor Agonist, Exerts Analgesic, Anti-Inflammatory and Anti-Degradative Actions in Osteoarthritis","volume":"12","author":"Meurot","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Li, S., Eguchi, N., Lau, H., and Ichii, H. (2020). The Role of the Nrf2 Signaling in Obesity and Insulin Resistance. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186973"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Di Veroli, B., Bentanachs, R., Roglans, N., Alegret, M., Giona, L., Profumo, E., Berry, A., Saso, L., Laguna, J.C., and Buttari, B. (2024). Sex Differences Affect the NRF2 Signaling Pathway in the Early Phase of Liver Steatosis: A High-Fat-Diet-Fed Rat Model Supplemented with Liquid Fructose. Cells, 13.","DOI":"10.3390\/cells13151247"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"709","DOI":"10.5650\/jos.ess21389","article-title":"Protective Effect of Nimbolide against High Fat Diet-Induced Obesity in Rats via Nrf2\/HO-1 Pathway","volume":"71","author":"Zhang","year":"2022","journal-title":"J. Oleo Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/1758-5996-6-130","article-title":"Metabolic and Oxidative Stress Markers in Wistar Rats after 2 Months on a High-Fat Diet","volume":"6","author":"Auberval","year":"2014","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-5996-3-17","article-title":"Biochemical Study of Oxidative Stress Markers in the Liver, Kidney and Heart of High Fat Diet Induced Obesity in Rats","volume":"3","author":"Noeman","year":"2011","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"20026","DOI":"10.1038\/s41598-019-56538-0","article-title":"High-Fat Diet-Induced Metabolic Syndrome and Oxidative Stress in Obese Rats Are Ameliorated by Yogurt Supplementation","volume":"9","author":"Lasker","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Albitar, O., D\u2019Souza, C.M., and Adeghate, E.A. (2024). Effects of Lipoproteins on Metabolic Health. Nutrients, 16.","DOI":"10.3390\/nu16132156"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1182\/blood-2006-09-048033","article-title":"Inhibition of HMGcoA Reductase by Atorvastatin Prevents and Reverses MYC-Induced Lymphomagenesis","volume":"110","author":"Shachaf","year":"2007","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.jare.2024.12.020","article-title":"Advances in Statin Adverse Reactions and the Potential Mechanisms: A Systematic Review","volume":"76","author":"Zeng","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Xiang, L., Wu, H., Zhao, Z., Wu, T., Lv, D., Wu, P., Zheng, Y., Huang, Q., and Xu, T. (2025). Lipid-Lowering Effect of Combined Therapy with High-Intensity Statins and CETP Inhibitors: A Systematic Review and Meta-Analysis. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1512670"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4773","DOI":"10.3748\/wjg.v16.i38.4773","article-title":"Hepatic Steatosis, Low-Grade Chronic Inflammation and Hormone\/Growth Factor\/Adipokine Imbalance","volume":"16","author":"Tarantino","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Zatterale, F., Longo, M., Naderi, J., Raciti, G.A., Desiderio, A., Miele, C., and Beguinot, F. (2020). Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01607"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Peng, S., Xu, L.W., Che, X.Y., Xiao, Q.Q., Pu, J., Shao, Q., and He, B. (2018). Atorvastatin Inhibits Inflammatory Response, Attenuates Lipid Deposition, and Improves the Stability of Vulnerable Atherosclerotic Plaques by Modulating Autophagy. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00438"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"bbaf241","DOI":"10.1093\/bib\/bbaf241","article-title":"Multi-Omics Analysis of Helicobacter Pylori-Associated Gastric Cancer Identifies Hub Genes as a Novel Therapeutic Biomarker","volume":"26","author":"Mohamed","year":"2025","journal-title":"Brief. Bioinform."},{"key":"ref_87","unstructured":"Ramanathan, K., Antognini, D., Combes, A., Paden, M., Zakhary, B., Ogino, M., Maclaren, G., and Brodie, D. (2026, March 23). Since January 2020 Elsevier Has Created a COVID-19 Resource Centre with Free Information in English and Mandarin on the Novel Coronavirus COVID-Research That Is Available on the COVID-19 Resource Centre-Including This for Unrestricted Research Re-Use a. 2020, 19\u201321. Available online: https:\/\/cmscscholar.org\/wp-content\/uploads\/2020\/06\/Giovanonni-COVID-MS.pdf."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"103","DOI":"10.2147\/CIA.S40405","article-title":"Atorvastatin Attenuates the Production of IL-1\u03b2, IL-6, and TNF-\u03b1 in the Hippocampus of an Amyloid \u03921-42-Induced Rat Model of Alzheimer\u2019s Disease","volume":"8","author":"Li","year":"2013","journal-title":"Clin. Interv. Aging"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Chan, P.C., Liao, M.T., and Hsieh, P.S. (2019). The Dualistic Effect of COX-2-Mediated Signaling in Obesity and Insulin Resistance. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133115"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Korovila, I., H\u00f6hn, A., Jung, T., Grune, T., and Ott, C. (2021). Reduced Liver Autophagy in High-Fat Diet Induced Liver Steatosis in New Zealand Obese Mice. Antioxidants, 10.","DOI":"10.3390\/antiox10040501"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"565","DOI":"10.2131\/jts.44.565","article-title":"Immunohistochemical Expression of Autophagosome Markers LC3 and P62 in Preneoplastic Liver Foci in High Fat Diet-Fed Rats","volume":"44","author":"Masuda","year":"2019","journal-title":"J. Toxicol. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Friuli, M., Sepe, C., Panza, E., Travelli, C., Paterniti, I., and Romano, A. (2024). Autophagy and Inflammation an Intricate Affair in the Management of Obesity and Metabolic Disorders: Evidence for Novel Pharmacological Strategies?. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1407336"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Elsiad, E.A., Abd El Aal, H.A., Salem, H.A., El-Yamany, M.F., and Rabie, M.A. (2025). Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats. Toxics, 13.","DOI":"10.3390\/toxics13070594"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/4\/490\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T08:03:59Z","timestamp":1776758639000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/4\/490"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":93,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["pharmaceutics18040490"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18040490","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]}}}