{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:01:19Z","timestamp":1785427279860,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004172","name":"Mersin University","doi-asserted-by":"crossref","award":["2024-TP2-5071"],"award-info":[{"award-number":["2024-TP2-5071"]}],"id":[{"id":"10.13039\/501100004172","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2024-TP2-5071"],"award-info":[{"award-number":["2024-TP2-5071"]}],"id":[{"id":"https:\/\/ror.org\/04nqdwb39","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Methotrexate (MTX) is widely used in the treatment of malignancies and inflammatory disorders, but nephrotoxicity remains a major adverse effect. Naringenin (NAR), a natural flavonoid, has antioxidant, anti-inflammatory, and nephroprotective properties. This study investigated the potential protective effects of NAR against MTX-induced nephrotoxicity at biochemical, molecular, and histopathological levels. Forty-two adult male Wistar albino rats were assigned to seven groups (n = 6): Control, CMC (carboxymethyl cellulose), NAR100, MTX, and MTX combined with NAR (25, 50, or 100 mg\/kg\/day). NAR was administered for 7 days, with MTX given on day 3. Renal function, histopathology, and genes associated with oxidative stress, apoptosis, endoplasmic reticulum stress, and inflammation were evaluated. MTX administration caused marked renal damage, increased creatinine and BUN levels, elevated apoptosis-, inflammation-, and ER stress-related gene expression, and suppressed antioxidant defense-related genes. However, 50 and 100 mg\/kg\/day NAR attenuated these alterations, with greater effects at 100 mg\/kg\/day. Histopathological damage was attenuated by NAR treatment, although complete recovery was not observed. These findings suggest that NAR may protect against MTX-induced nephrotoxicity through the modulation of pathways associated with oxidative stress, inflammation, apoptosis, and ER stress. However, the persistence of certain histopathological alterations indicates that structural recovery of renal tissue may take a longer period compared with molecular changes.<\/jats:p>","DOI":"10.3390\/ijms27135973","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T07:59:47Z","timestamp":1783065587000},"page":"5973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Naringenin Attenuates Methotrexate-Induced Nephrotoxicity Accompanied by Alterations in Oxidative Stress, Inflammatory, Apoptotic, and Endoplasmic Reticulum Stress Responses"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7792-6505","authenticated-orcid":false,"given":"Arzum","family":"Arzu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Toxicology, Institute of Health Sciences, Mersin University, Mersin 33343, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3244-4103","authenticated-orcid":false,"given":"Zuhal Uckun","family":"Sahinogullari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Mersin University, Mersin 33169, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1270-2408","authenticated-orcid":false,"given":"Serife Efsun","family":"Antmen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin 33169, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5861-8538","authenticated-orcid":false,"given":"Gokhan","family":"Nur","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Iskenderun Technical University, Hatay 31200, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0247-6462","authenticated-orcid":false,"given":"Safak","family":"Sandayuk","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Faculty of Science and Arts, Kafkas University, Kars 36100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1177\/1091581819831701","article-title":"Kidney pathophysiology, toxicology, and drug-induced injury in drug development","volume":"38","author":"Radi","year":"2019","journal-title":"Int. J. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.2215\/CJN.00150118","article-title":"Pharmacology behind common drug nephrotoxicities","volume":"13","author":"Perazella","year":"2018","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/bs.acr.2022.03.005","article-title":"Nephrotoxicity in cancer treatment: An update","volume":"155","author":"Chen","year":"2022","journal-title":"Adv. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"151682","DOI":"10.1016\/j.acthis.2021.151682","article-title":"Evaluation of the effect of methotrexate on the hippocampus, cerebellum, liver, and kidneys of adult male albino rat: Histopathological, immunohistochemical and biochemical studies","volume":"123","author":"Ahmed","year":"2021","journal-title":"Acta Histochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112180","DOI":"10.1016\/j.biopha.2021.112180","article-title":"Nephroprotective effect of naringin in methotrexate induced renal toxicity in male rats","volume":"143","author":"Elsawy","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"103517","DOI":"10.1016\/j.tice.2026.103517","article-title":"Mangiferin ameliorates methotrexate-induced nephrotoxicity via suppression of oxidative inflammation, caspase apoptosis and genotoxicity in rats","volume":"101","author":"Eljarwany","year":"2026","journal-title":"Tissue Cell"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fahmy, M.M., Habib, H.A., Zeidan, E.M., Jardan, Y.A.B., and Heeba, G.H. (2025). Alogliptin mitigates methotrexate-induced nephrotoxicity in a rat model: Antagonizing oxidative stress, inflammation and apoptosis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199608"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1080\/01480545.2024.2429616","article-title":"Assessment of morin hydrate as a renal protective agent in rats subjected to methotrexate-induced nephrotoxicity","volume":"48","author":"Caglayan","year":"2025","journal-title":"Drug. Chem. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/s12013-023-01168-7","article-title":"Infliximab ameliorates methotrexate-induced nephrotoxicity in experimental rat model: Impact on oxidative stress, mitochondrial biogenesis, apoptotic and autophagic machineries","volume":"81","author":"Wasfey","year":"2023","journal-title":"Cell Biochem. Biophys."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Cheng, C., Yuan, Y., Yuan, F., and Li, X. (2024). Acute kidney injury: Exploring endoplasmic reticulum stress-mediated cell death. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1308733"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","article-title":"Mechanisms, regulation and functions of the unfolded protein response","volume":"21","author":"Hetz","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1080\/01480545.2018.1512612","article-title":"Potential protective effects of naringenin against vancomycin-induced nephrotoxicity via reduction on apoptotic and oxidative stress markers in rats","volume":"43","author":"Uckun","year":"2020","journal-title":"Drug Chem. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"191","DOI":"10.33808\/clinexphealthsci.741916","article-title":"Naringenin reduces hepatic inflammation and apoptosis induced by vancomycin in rats","volume":"11","author":"Guzel","year":"2021","journal-title":"Clin. Exp. Health Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4075","DOI":"10.1002\/ptr.7071","article-title":"A review on the protective effects of naringenin against natural and chemical toxic agents","volume":"35","author":"Naraki","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.nutres.2023.08.006","article-title":"Biological activities of naringenin: A narrative review based on in vitro and in vivo studies","volume":"119","year":"2023","journal-title":"Nutr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.etap.2014.07.015","article-title":"Protective effect of naringenin against gentamicin-induced nephrotoxicity in rats","volume":"38","author":"Fouad","year":"2014","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e12398","DOI":"10.1111\/jfbc.12398","article-title":"Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties","volume":"41","author":"Kandemir","year":"2017","journal-title":"J. Food. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Stabrauskiene, J., Kopustinskiene, D.M., Lazauskas, R., and Bernatoniene, J. (2022). Naringin and naringenin: Their mechanisms of action and the potential anticancer activities. Biomedicines, 10.","DOI":"10.3390\/biomedicines10071686"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"114606","DOI":"10.1016\/j.biopha.2023.114606","article-title":"Cellular red-ox system in health and disease: The latest update","volume":"162","author":"Jena","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_20","first-page":"22","article-title":"Protective effects of sitagliptin on methotrexate-induced nephrotoxicity in rats","volume":"41","author":"Malekinejad","year":"2023","journal-title":"J. Environ. Sci. Health C Toxicol. Carcinog."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2474831","DOI":"10.1155\/2018\/2474831","article-title":"Nephroprotective effect of zingerone against CCl4-induced renal toxicity in swiss albino mice: Molecular mechanism","volume":"2018","author":"Safhi","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.biopha.2018.10.088","article-title":"The impact of Keap1\/Nrf2, P38MAPK\/NF-\u03baB and Bax\/Bcl2\/caspase-3 signaling pathways in the protective effects of berberine against methotrexate-induced nephrotoxicity","volume":"109","author":"Hassanein","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s44337-025-00315-8","article-title":"Advancing nephroprotective strategies: The role of naringenin in preventing gentamicin-induced nephrotoxicity","volume":"2","author":"Bwambale","year":"2025","journal-title":"Discov. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.fct.2018.03.041","article-title":"Renoprotective effects of umbelliferone on methotrexate-induced renal injury through regulation of Nrf-2\/Keap-1, P38MAPK\/NF-\u03baB, and apoptosis signaling pathways","volume":"116","author":"Hassanein","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"105371","DOI":"10.1016\/j.phrs.2020.105371","article-title":"Interaction of nobiletin with methotrexate ameliorates 7-OH methotrexate-induced nephrotoxicity through endoplasmic reticulum stress-dependent PERK\/CHOP signaling pathway","volume":"165","author":"Song","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"110465","DOI":"10.1016\/j.abb.2025.110465","article-title":"Nephroprotective effects of hesperidin on ifosfamide-induced acute nephrotoxicity in rats: Role of NF-\u03baB\/TNF-\u03b1\/IL-1\u03b2, p53\/caspase-3\/Bax\/Bcl-2, and ATF6\/IRE1\/PERK\/GRP78 signaling pathways","volume":"770","author":"Kandemir","year":"2025","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.molcel.2017.06.017","article-title":"The unfolded protein response and cell fate control","volume":"69","author":"Hetz","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"122","DOI":"10.4103\/0973-7847.134247","article-title":"Cytotoxicity of dietary flavonoids on different human cancer types","volume":"8","author":"Sak","year":"2014","journal-title":"Pharmacogn. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1007\/s12017-008-8037-y","article-title":"Hormetic dietary phytochemicals","volume":"10","author":"Son","year":"2008","journal-title":"Neuromolecular. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.arr.2007.08.007","article-title":"Hormesis defined","volume":"7","author":"Mattson","year":"2008","journal-title":"Ageing Res. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ncb0311-184","article-title":"Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress","volume":"13","author":"Tabas","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Han, Y., Yuan, M., Guo, Y.S., Shen, X.Y., Gao, Z.K., and Bi, X. (2021). Mechanism of endoplasmic reticulum stress in cerebral ischemia. Front. Cell. Neurosci., 15.","DOI":"10.3389\/fncel.2021.704334"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"114791","DOI":"10.1016\/j.fct.2024.114791","article-title":"The ameliorative effects of chrysin on bortezomib-induced nephrotoxicity in rats: Reduces oxidative stress, endoplasmic reticulum stress, inflammation damage, apoptotic and autophagic death","volume":"190","author":"Akaras","year":"2024","journal-title":"Food. Chem. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7615","DOI":"10.1007\/s00210-025-04846-w","article-title":"Apremilast ameliorates methotrexate-induced renal injury in rats: Role of TLR4\/NF-\u03baB\/P38 MAPK\/caspase-3 and Nrf2\/HO-1 signaling pathways","volume":"399","author":"Mohyeldin","year":"2026","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s10735-025-10697-9","article-title":"Curcumin treatment attenuates methotrexate-induced nephrotoxicity in rats by inhibiting inflammation and fibrosis","volume":"57","author":"Uz","year":"2026","journal-title":"J. Mol. Histol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"114911","DOI":"10.1016\/j.fct.2024.114911","article-title":"The ameliorative effect of Naringenin on fenamiphos-induced hepatotoxicity and nephrotoxicity in a rat model: Oxidative stress, inflammatory markers, biochemical, histopathological, immunohistochemical and electron microscopy study","volume":"192","author":"Karaboduk","year":"2024","journal-title":"Food. Chem. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/cpt.726","article-title":"The nephrotoxicity of vancomycin","volume":"102","author":"Filippone","year":"2017","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1634\/theoncologist.2015-0164","article-title":"preventing and managing toxicities of high-dose methotrexate","volume":"21","author":"Howard","year":"2016","journal-title":"Oncologist"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1111\/fcp.12205","article-title":"Protective mechanisms of resveratrol against methotrexate-induced renal damage may involve BCRP\/ABCG2","volume":"30","author":"Morsy","year":"2016","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using realtime quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_41","unstructured":"Presnell, J., and Schreibman, M.P. (1997). Humason\u2019s Animal Tissue Techniques, Johns Hopkins University Press. [5th ed.]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5973\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T04:14:12Z","timestamp":1783224852000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":41,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135973"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135973","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,3]]}}}