{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T11:13:44Z","timestamp":1781349224640,"version":"3.54.1"},"reference-count":58,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T00:00:00Z","timestamp":1694390400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100007128","name":"Natural Science Foundation of Shaanxi Province","doi-asserted-by":"publisher","award":["2022JQ\u2010825"],"award-info":[{"award-number":["2022JQ\u2010825"]}],"id":[{"id":"10.13039\/501100007128","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environmental Toxicology"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Due to the high abundance in the Earth's crust and industrial application, fluoride is widely present in our living environment. However, excessive fluoride exposure causes toxicity in different organs. As the most important detoxification and excretion organ, liver is more easily involved in fluoride toxicity than other organs, and oxidative stress is considered as the key mechanism related with fluoride hepatotoxicity. In this study, we mainly investigated the role of nuclear factor erythroid\u2010derived 2\u2010like 2 (NRF2, a core transcription factor in oxidative stress) in fluoride exposure\u2010induced hepatotoxicity as well as the related mechanism. Herein, liver cells (BNL CL.2) were treated with fluoride in different concentrations. The hepatotoxicity and NRF2 signaling pathway were analyzed respectively. Our results indicated that excessive fluoride (over 1\u2009mM) resulted in obvious toxicity in hepatocyte and activated NRF2 and NRF2 target genes. The increased ROS generation after fluoride exposure suppressed KEAP1\u2010induced NRF2 ubiquitylation and degradation. Meanwhile, fluoride exposure also led to blockage of autophagic flux and upregulation of p62, which contributed to activation of NRF2 via competitive binding with KEAP1. Both pharmaceutical activation and genetic activation of NRF2 accelerated fluoride exposure\u2010induced hepatotoxicity. Thus, the upregulation of NRF2 in hepatocyte after fluoride exposure can be regarded as a cellular self\u2010defense, and NRF2\u2010KEAP1 system could be a novel molecular target against fluoride exposure\u2010induced hepatotoxicity.<\/jats:p>","DOI":"10.1002\/tox.23954","type":"journal-article","created":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T12:04:18Z","timestamp":1694433858000},"page":"252-263","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Fluoride exposure confers <scp>NRF2<\/scp> activation in hepatocyte through both canonical and non\u2010canonical signaling pathways"],"prefix":"10.1002","volume":"39","author":[{"given":"Miaomiao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Regenerative Medicine School of Pharmaceutical Science, Jilin University  Changchun China"},{"name":"National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine School of Pharmaceutical Science, Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Liu","sequence":"additional","affiliation":[{"name":"National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"},{"name":"International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjiao","family":"Shi","sequence":"additional","affiliation":[{"name":"National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"},{"name":"International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic &amp; Splenic Diseases The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yishu","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Second School of Clinical Medicine Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixuan","family":"Zeng","sequence":"additional","affiliation":[{"name":"National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"},{"name":"International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongguo","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Nephrology Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5818-8004","authenticated-orcid":false,"given":"Pengfei","family":"Liu","sequence":"additional","affiliation":[{"name":"National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"},{"name":"International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic &amp; Splenic Diseases The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"},{"name":"Key Laboratory of Environment and Genes Related to Diseases Xi'an Jiaotong University, Ministry of Education of China  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034519843495"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2019.06.045"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2018.04.002"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2022.156058"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2015.05.126"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2018.09.010"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2021.150184"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2020.110962"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010818-021856"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29219"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.1.76"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.24.10941-10953.2004"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3211"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.096545"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00248-10"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2021"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2015.06.007"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7356"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30616"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemosphere.2019.125495"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2015.07.003"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aquatox.2019.06.002"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3109\/15376516.2015.1025348"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00128-014-1271-0"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-010-0588-7"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpc.2022.109526"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2023.114646"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2019.04.409"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/tox.22636"},{"key":"e_1_2_10_31_1","first-page":"2269","article-title":"Borassus flabellifer Linn haustorium methanol extract mitigates fluoride\u2010induced apoptosis by enhancing Nrf2\/Haeme oxygenase 1\u2010dependent glutathione metabolism in intestinal epithelial cells","volume":"1","author":"Job JT","year":"2021","journal-title":"Drug Chem Toxicol"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/tox.22928"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2019.01.001"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00037-19"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-020-1897-0"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1812125115"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00660-16"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2019.07.011"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2017.06.018"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/tox.22495"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2022.113672"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2022.119241"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2021.150601"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemosphere.2019.125099"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/tox.23301"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.03.022"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-019-05050-9"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1177\/0960327119842273"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2019.01.016"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01748-12"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxrep.2014.01.002"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2016.07.022"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00267"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102570"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2022.08.004"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2020.110605"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2022.113764"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2022.109870"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.04.007"}],"container-title":["Environmental Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/tox.23954","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T15:15:29Z","timestamp":1704813329000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/tox.23954"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,11]]},"references-count":58,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1002\/tox.23954"],"URL":"https:\/\/doi.org\/10.1002\/tox.23954","archive":["Portico"],"relation":{},"ISSN":["1520-4081","1522-7278"],"issn-type":[{"value":"1520-4081","type":"print"},{"value":"1522-7278","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,11]]},"assertion":[{"value":"2023-02-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}