{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:03:09Z","timestamp":1784167389175,"version":"3.55.0"},"reference-count":29,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"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: Doxorubicin is an effective antineoplastic agent, but its use is constrained by off-target toxicities, including acute liver injury driven by mitochondrial dysfunction, oxidative stress, sterile inflammation, and redox-sensitive signaling pathways. Exenatide, a glucagon-like peptide-1 receptor agonist, exerts antioxidant and anti-inflammatory effects in several experimental liver injury models, but its role in doxorubicin-induced hepatic injury has not been investigated to our knowledge. This study evaluated whether exenatide attenuates acute doxorubicin-induced hepatic injury and examined whether the observed biochemical changes are consistent with modulation of oxidative stress and SIRT1\u2013HMGB1\/NF-\u03baB-related signaling. Methods: Male Wistar albino rats were allocated to four groups (n = 7\/group): control, exenatide, doxorubicin, and exenatide + doxorubicin. Exenatide (10 \u00b5g\/kg\/day, intraperitoneally) was administered for seven days. Doxorubicin was given intraperitoneally on days 5\u20137 at a cumulative dose of 18 mg\/kg. The pretreatment design was used to test preventive attenuation rather than reversal of established injury. Hepatic injury-associated enzyme activities, serum HMGB1, hepatic SIRT1, NF-\u03baB, TNF-\u03b1, IL-6, IL-10, malondialdehyde, glutathione, total antioxidant status, total oxidant status, nitric oxide, and hepatic 99mTc-pyrophosphate uptake were assessed. Results: Doxorubicin substantially increased intrahepatic ALT and AST activities, serum HMGB1, hepatic NF-\u03baB, TNF-\u03b1, IL-6, malondialdehyde, total oxidant status, nitric oxide, and hepatic 99mTc-pyrophosphate uptake, while reducing SIRT1, IL-10, glutathione, and total antioxidant status. Relative to the doxorubicin group, exenatide lowered HMGB1 by 48.3%, hepatic 99mTc-pyrophosphate uptake by 48.7%, malondialdehyde by 45.0%, total oxidant status by 37.3%, nitric oxide by 40.7%, NF-\u03baB by 40.4%, TNF-\u03b1 by 48.6%, and IL-6 by 41.1%, while increasing SIRT1 by 91.7%, IL-10 by 115%, glutathione by 115%, and total antioxidant status by 87.8%. None of the altered parameters returned completely to control levels, indicating attenuation rather than full normalization of acute injury-related changes. Conclusions: Exenatide attenuated doxorubicin-induced acute hepatic injury in this rat model and was associated with reduced oxidative stress, reduced inflammatory activation, higher hepatic SIRT1 levels, lower serum HMGB1 levels, and reduced hepatic 99mTc-pyrophosphate uptake. The findings are consistent with involvement of SIRT1\u2013HMGB1\/NF-\u03baB-related signaling, but they do not establish causality. Hepatic 99mTc-pyrophosphate uptake should be interpreted as an exploratory imaging correlate of tissue injury rather than an established liver biomarker. Additional studies incorporating histopathology, immunohistochemistry, functional liver indices, mechanistic validation of SIRT1, and tumor-bearing models are required before translational conclusions can be drawn.<\/jats:p>","DOI":"10.3390\/ph19071086","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:05:07Z","timestamp":1784163907000},"page":"1086","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exenatide Attenuates Doxorubicin-Induced Acute Hepatic Injury Through Modulation of SIRT1-HMGB1 Signaling and Oxidative Stress"],"prefix":"10.3390","volume":"19","author":[{"given":"Haluk Kerim","family":"Karakullukcu","sequence":"first","affiliation":[{"name":"Department of General Surgery, Sultan 2. Abdulhamid Han Educational and Research Hospital, University of Health Sciences, Istanbul 34668, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4822-2588","authenticated-orcid":false,"given":"Serdar Sava\u015f","family":"G\u00fcl","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Faculty of Medicine, Lokman Hekim University, Ankara 06530, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4272-0562","authenticated-orcid":false,"given":"Hatice","family":"Aygun","sequence":"additional","affiliation":[{"name":"Neuroscience Laboratory, BAMER, Biruni University, Istanbul 34010, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2311-9413","authenticated-orcid":false,"given":"Murat","family":"Kal\u0131n","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Sultan 2. Abdulhamid Han Educational and Research Hospital, University of Health Sciences, Istanbul 34668, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Karakullukcu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sultan 2. Abdulhamid Han Educational and Research Hospital, University of Health Sciences, Istanbul 34668, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aylin","family":"Arslan","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Istanbul Prof. Dr. Cemil Ta\u015f\u00e7\u0131o\u011flu City Hospital, Health Sciences University, Istanbul 34668, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6mer Faruk","family":"\u00d6zkan","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Sultan 2. Abdulhamid Han Educational and Research Hospital, University of Health Sciences, Istanbul 34668, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcl\u00e7in","family":"Ercan","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Sultan 2. Abdulhamid Han Educational and Research Hospital, University of Health Sciences, Istanbul 34668, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Radeva, L., and Yoncheva, K. (2025). Doxorubicin toxicity and recent approaches to alleviating its adverse effects with focus on oxidative stress. Molecules, 30.","DOI":"10.3390\/molecules30153311"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"117599","DOI":"10.1016\/j.lfs.2020.117599","article-title":"New molecular and biochemical insights of doxorubicin-induced hepatotoxicity","volume":"250","author":"Prasanna","year":"2020","journal-title":"Life Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10125","DOI":"10.1007\/s00210-025-03808-6","article-title":"Febuxostat protects from Doxorubicin induced hepatotoxicity in rats via regulation of NF-\u03baB p65\/NLRP3 inflammasome and SIRT-1\/AMPK pathways","volume":"398","author":"Yousef","year":"2025","journal-title":"Naunyn-Schmiedebergs Arch. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"106626","DOI":"10.1016\/j.jff.2024.106626","article-title":"Mitigation of doxorubicin-induced liver toxicity in mice breast cancer model by green tea and Moringa oleifera combination: Targeting apoptosis, inflammation, and oxidative stress","volume":"124","author":"Laftah","year":"2025","journal-title":"J. Funct. Foods"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"103308","DOI":"10.1016\/j.sjbs.2022.103308","article-title":"Doxorubicin-induced hepatic toxicity in rats: Mechanistic protective role of Omega-3 fatty acids through Nrf2\/HO-1 activation and PI3K\/Akt\/GSK-3\u03b2 axis modulation","volume":"29","author":"Saleh","year":"2022","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1002\/JLB.3MR0121-277R","article-title":"HMGB1: An overview of its roles in the pathogenesis of liver disease","volume":"110","author":"Ni","year":"2021","journal-title":"J. Leukoc. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e17094","DOI":"10.7717\/peerj.17094","article-title":"The role of sirtuin1 in liver injury: Molecular mechanisms and novel therapeutic target","volume":"12","author":"Wang","year":"2024","journal-title":"PeerJ"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wei, L., Zhang, W., Li, Y., and Zhai, J. (2022). The SIRT1-HMGB1 axis: Therapeutic potential to ameliorate inflammatory responses and tumor occurrence. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.986511"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Song, S., Chu, L., Liang, H., Chen, J., Liang, J., Huang, Z., Zhang, B., and Chen, X. (2019). Protective effects of dioscin against doxorubicin-induced hepatotoxicity via regulation of Sirt1\/FOXO1\/NF-\u03bab signal. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01030"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yang, Y., Liu, Y., Wang, Y., Chao, Y., Zhang, J., Jia, Y., Tie, J., and Hu, D. (2022). Regulation of SIRT1 and its roles in inflammation. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.831168"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1864307","DOI":"10.1155\/2018\/1864307","article-title":"Exenatide Delays the Progression of Nonalcoholic Fatty Liver Disease in C57BL\/6 Mice, Which May Involve Inhibition of the NLRP3 Inflammasome through the Mitophagy Pathway","volume":"2018","author":"Shao","year":"2018","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"117725","DOI":"10.1016\/j.lfs.2020.117725","article-title":"Exenatide ameliorates experimental non-alcoholic fatty liver in rats via suppression of toll-like receptor 4\/NF\u03baB signaling: Comparison to metformin","volume":"253","author":"Saad","year":"2020","journal-title":"Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1016\/j.ajpath.2012.07.015","article-title":"The glucagon-like peptide-1 receptor agonist Exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis","volume":"181","author":"Gupta","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3637","DOI":"10.2337\/db14-0263","article-title":"SIRT1 mediates the effect of GLP-1 receptor agonist exenatide on ameliorating hepatic steatosis","volume":"63","author":"Xu","year":"2014","journal-title":"Diabetes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15971","DOI":"10.1038\/srep15971","article-title":"Deacetylation-mediated interaction of SIRT1-HMGB1 improves survival in a mouse model of endotoxemia","volume":"5","author":"Hwang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0001-2998(82)80031-7","article-title":"Liver uptake of 99mTc-pyrophosphate","volume":"12","author":"Hansen","year":"1982","journal-title":"Semin. Nucl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1172\/JCI108825","article-title":"Sites and mechanisms of localization of technetium-99m phosphorus radiopharmaceuticals in acute myocardial infarcts and other tissues","volume":"60","author":"Buja","year":"1977","journal-title":"J. Clin. Investg."},{"key":"ref_19","first-page":"550","article-title":"Localization of Tc-99m-pyrophosphate in the liver due to massive liver necrosis: Case report","volume":"18","author":"Lyons","year":"1977","journal-title":"J. Nucl. Med."},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"H1466","DOI":"10.1152\/ajpheart.00795.2008","article-title":"Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro","volume":"296","author":"Mukhopadhyay","year":"2009","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/s00210-015-1124-3","article-title":"Exenatide (a GLP-1 agonist) improves the antioxidative potential of in vitro cultured human monocytes\/macrophages","volume":"388","author":"Machnik","year":"2015","journal-title":"Naunyn-Schmiedebergs Arch. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Arab, H.H., Eid, A.H., Alsufyani, S.E., Ashour, A.M., Alnefaie, A.M., Alsharif, N.M., Alshehri, A.M., Almalawi, A.A., Alsowat, A.A., and Abd El Aal, H.A. (2024). Activation of AMPK\/mTOR-Driven Autophagy and Suppression of the HMGB1\/TLR4 Pathway with Pentoxifylline Attenuates Doxorubicin-Induced Hepatic Injury in Rats. Pharmaceuticals, 17.","DOI":"10.3390\/ph17060681"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/hep.21006","article-title":"Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob\/ob mice","volume":"43","author":"Ding","year":"2006","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"428","DOI":"10.4161\/oxim.3.6.14416","article-title":"Doxorubicin toxicity can be ameliorated during antioxidant L-carnitine supplementation","volume":"3","author":"Alshabanah","year":"2010","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"281","DOI":"10.4149\/BLL_2024_42","article-title":"Electrocardiographic, biochemical, and scintigraphic evidence for the cardioprotective effect of paricalcitol and vitamin D3 on doxorubicin-induced acute cardiotoxicity in rats","volume":"125","author":"Koroglu","year":"2024","journal-title":"Bratisl. Med. J. Bratisl. Lek. Listy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"74","DOI":"10.4103\/2141-9248.126619","article-title":"An evaluation of hepatotoxicity in breast cancer patients receiving injection Doxorubicin","volume":"4","author":"Damodar","year":"2014","journal-title":"Ann. Med. Health Sci. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Podyacheva, E.Y., Kushnareva, E.A., Karpov, A.A., and Toropova, Y.G. (2021). Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View from the Perspective of the Pathophysiologist and the Clinician. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.670479"},{"key":"ref_29","first-page":"649","article-title":"Cardioprotective effect of vitamin D and melatonin on doxorubicin-induced cardiotoxicity in rat model: An electrocardiographic, scintigraphic and biochemical study","volume":"5","year":"2018","journal-title":"Eur. Res. J."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1086\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:08:42Z","timestamp":1784164122000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1086"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":29,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ph19071086"],"URL":"https:\/\/doi.org\/10.3390\/ph19071086","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,15]]}}}