{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:16:24Z","timestamp":1791594984437,"version":"4.3.4"},"reference-count":45,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,7,2]],"date-time":"2023-07-02T00:00:00Z","timestamp":1688256000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81660593"],"award-info":[{"award-number":["81660593"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Emodin has been demonstrated to possess multiple pharmacological activities. However, emodin has also been reported to induce nephrotoxicity at high doses and with long\u2010term use, and the underlying mechanism has not been fully disclosed. The current study aimed to investigate the roles of oxidative stress and ferroptosis in emodin\u2010induced kidney toxicity. Mice were intraperitoneally treated with emodin, and NRK\u201052E cells were exposed to emodin in the presence or absence of treatment with Jagged1, SC79, or t\u2010BHQ. Emodin significantly upregulated the levels of blood urea nitrogen, serum creatinine, malondialdehyde, and Fe<jats:sup>2+<\/jats:sup>, reduced the levels of superoxide dismutase and glutathione, and induced pathological changes in the kidneys in vivo. Moreover, the viability of NRK\u201052E cells treated with emodin was reduced, and emodin induced iron accumulation, excessive reactive oxygen species production, and lipid peroxidation and depolarized the mitochondrial membrane potential (<jats:italic>\u0394\u03a8m<\/jats:italic>). In addition, emodin treatment downregulated the activity of neurogenic locus notch homolog protein 1 (Notch1), reduced the nuclear translocation of nuclear factor erythroid\u20102 related factor 2 (Nrf2), and decreased glutathione peroxidase 4 protein levels. However, Notch1 activation by Jagged1 pretreatment, Akt activation by SC79 pretreatment, or Nrf2 activation by t\u2010BHQ pretreatment attenuated the toxic effects of emodin in NRK\u201052E cells. Taken together, these results revealed that emodin\u2010induced ferroptosis triggered kidney toxicity through inhibition of the Notch1\/Nrf2\/glutathione peroxidase 4 axis.<\/jats:p>","DOI":"10.1002\/jat.4509","type":"journal-article","created":{"date-parts":[[2023,7,2]],"date-time":"2023-07-02T18:43:51Z","timestamp":1688323431000},"page":"1702-1718","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Emodin disrupts the Notch1\/Nrf2\/GPX4 antioxidant system and promotes renal cell ferroptosis"],"prefix":"10.1002","volume":"43","author":[{"given":"Miao","family":"Xing","sequence":"first","affiliation":[{"name":"School of Medicine Yichun University  Yichun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Medicine Yichun University  Yichun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine Yichun University  Yichun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoze","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine Yichun University  Yichun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjuan","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Medicine Yichun University  Yichun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine Yichun University  Yichun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Medicine Yichun University  Yichun China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-020-01977-0"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2021.04.030"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/5638943"},{"issue":"5","key":"e_1_2_10_5_1","first-page":"609","article-title":"In vitro study of the nephrotoxicity of total Dahuang (Radix Et Rhizoma Rhei Palmati) anthraquinones and emodin in monolayer human proximal tubular epithelial cells cultured in a transwell chamber","volume":"39","author":"Cao C.","year":"2019","journal-title":"Journal of Traditional Chinese Medicine"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0192415X96000189"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-018-4005-4"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.624529"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00962"},{"issue":"9","key":"e_1_2_10_10_1","first-page":"4571","article-title":"Protective effects of the AKT activator SC79 on renal ischemia\u2010reperfusion injury","volume":"11","author":"Dong D.","year":"2018","journal-title":"International Journal of Clinical and Experimental Pathology"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.5631"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5484"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.10.086"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomed.2012.03.003"},{"issue":"11","key":"e_1_2_10_15_1","first-page":"42","article-title":"Apoptosis mechanism of emodin on renal toxicity in mice","volume":"25","author":"Huang W.","year":"2019","journal-title":"Chinese Journal of Experimental Traditional Medical Formulae"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/82_2016_508"},{"issue":"6","key":"e_1_2_10_17_1","first-page":"91","article-title":"Research progress on emodin hepatorenal toxicity","volume":"40","author":"Ji W. 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