{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T06:47:50Z","timestamp":1782110870342,"version":"3.54.5"},"reference-count":50,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Nephrotoxicity is one of the most significant therapeutic limitations of gentamicin (GM) antibiotics, strongly linked to oxidative stress and apoptotic pathways. In this study, diacerein (DIA), an antiarthritic agent with potent antioxidant and anti\u2010inflammatory properties, was investigated for its renoprotective potential and underlying mechanisms in GM\u2010induced nephrotoxicity. Rats received GM (100\u2009mg\/kg, i.p.) alone or with DIA (25 or 50\u2009mg\/kg) for 10 days. Kidney tissues were assessed for histological damage, oxidative stress, apoptotic and inflammatory markers, and key signaling pathway activities. Structural equation modeling (SEM) was performed to explore mechanistic interactions and biomarker predictive. In a dose\u2010dependent manner, DIA mitigated renal histopathological disturbance and attenuated the imbalanced oxidative status in GM\u2010challenged rats by reducing renal MDA levels, as well as stimulating catalase and SOD activities and Nrf2 protein expression. DIA also attenuated GM\u2010induced inflammation and apoptosis by suppressing NF\u2010\u03baB and cleaved caspase\u20103 expression. DIA restoration of phosphorylated PI3K and AKT protein expression, suggesting activation of the PI3K\/AKT\/Nrf2\/NF\u2010\u03baB signaling pathway. Principal component analysis (PCA) extracted one dominant component (PC1) as the antioxidant\u2013oxidative stress axis, explaining over 90% of the total variance. SEM further supported a mechanistic framework wherein PI3K strongly influenced AKT, which upregulated Nrf2 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20090.66,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) and, in turn, enhanced CAT and SOD (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20090.86 and 0.83,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). The model reinforces AKT\u2013Nrf2\u2013CAT axis as a critical pathway modulating caspase\u2010dependent apoptosis. DIA exhibits renal protection in GM\u2010induced nephrotoxicity mainly through modulating PI3K\/AKT\/Nrf2 signaling pathways. PCA and SEM analyses provide novel mechanistic and diagnostic insights that enhance the translational potential of the findings.\n                  <\/jats:p>","DOI":"10.1002\/jbt.70945","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T07:29:13Z","timestamp":1781594953000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diacerein Ameliorates Gentamicin\u2010Induced Nephrotoxicity via Regulating PI3k\/AKT\u2010Mediated Nrf\u20102 and NF\u2010\u03baB Pathways: Forge the Mechanistic Insight"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7933-2344","authenticated-orcid":false,"given":"Heba A.","family":"Habib","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy, Minia University El\u2010Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gehan H.","family":"Heeba","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy, Minia University El\u2010Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3770-7128","authenticated-orcid":false,"given":"Rania","family":"Abdel\u2010latif","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy, Minia University El\u2010Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2010.337"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-6915(03)00186-8"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2013.10.002"},{"key":"e_1_2_12_5_1","first-page":"388","article-title":"Gentamicin Nephrotoxicity in Animals: Current Knowledge and Future Perspectives","volume":"16","author":"Randjelovic P.","year":"2017","journal-title":"EXCLI Journal"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2019020204"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.21608\/besps.2020.34565.1065"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2014.02.022"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21134777"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2008.12.055"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12013-022-01064-6"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2021.153466"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD005117.pub3"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2019.04.008"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-022-07366-5"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2021.08.025"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2022.103907"},{"key":"e_1_2_12_19_1","first-page":"1","article-title":"Involvement of Oxidative Stress and Toll\u2010Like Receptor\u20104 Signaling Pathways in Gentamicin\u2010Induced Nephrotoxicity in Male Sprague Dawley Rats","volume":"45","author":"Pakfetrat Z.","year":"2021","journal-title":"Drug and Chemical Toxicology"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.4103\/0976-500X.119726"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/9507563"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.4067\/S0717-95022023000200625"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.122080"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13944"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0962728600005492"},{"key":"e_1_2_12_26_1","volume-title":"Bancroft's Theory and Practice of Histological Techniques E\u2010Book","author":"Suvarna K. 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