{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:41:43Z","timestamp":1789015303625,"version":"build-2803163510"},"reference-count":46,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T00:00:00Z","timestamp":1705104000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T00:00:00Z","timestamp":1705104000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Drug\u2010induced liver injury (DILI) is one of the most frequent reasons for failure of drugs in clinical trials or market withdrawal. Early assessment of DILI risk remains a major challenge during drug development. Here, we present a mechanism\u2010based weight\u2010of\u2010evidence approach able to identify certain candidate compounds with DILI liabilities due to mitochondrial toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 1587 FDA\u2010approved drugs and 378 kinase inhibitors were screened for cellular stress response activation associated with DILI using an imaging\u2010based HepG2 BAC\u2010GFP reporter platform including the integrated stress response (CHOP), DNA damage response (P21) and oxidative stress response (SRXN1).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In total 389, 219 and 104 drugs were able to induce CHOP\u2010GFP, P21\u2010GFP and SRXN1\u2010GFP expression at 50\u2009\u03bcM respectively. Concentration response analysis identified 154 FDA\u2010approved drugs as critical CHOP\u2010GFP inducers. Based on predicted and observed (pre\u2010)clinical DILI liabilities of these drugs, nine antimycotic drugs (e.g. butoconazole, miconazole, tioconazole) and 13 central nervous system (CNS) agents (e.g. duloxetine, fluoxetine) were selected for transcriptomic evaluation using whole\u2010genome RNA\u2010sequencing of primary human hepatocytes. Gene network analysis uncovered mitochondrial processes, NRF2 signalling and xenobiotic metabolism as most affected by the antimycotic drugs and CNS agents. Both the selected antimycotics and CNS agents caused impairment of mitochondrial oxygen consumption in both HepG2 and primary human hepatocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Together, the results suggest that early pre\u2010clinical screening for CHOP expression could indicate liability of mitochondrial toxicity in the context of DILI, and, therefore, could serve as an important warning signal to consider during decision\u2010making in drug development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.15822","type":"journal-article","created":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T04:40:07Z","timestamp":1705120807000},"page":"760-775","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The integrated stress response\u2010related expression of\n                    <i>CHOP<\/i>\n                    due to mitochondrial toxicity is a warning sign for\n                    <scp>DILI<\/scp>\n                    liability"],"prefix":"10.1111","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0910-8865","authenticated-orcid":false,"given":"Matthijs","family":"Vlasveld","sequence":"first","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Callegaro","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciar\u00e1n","family":"Fisher","sequence":"additional","affiliation":[{"name":"Certara UK Limited (Simcyp Division)  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Eakins","sequence":"additional","affiliation":[{"name":"Cyprotex Discovery Ltd.  Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Walker","sequence":"additional","affiliation":[{"name":"Cyprotex Discovery Ltd.  Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Lok","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddh","family":"van Oost","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brechtje","family":"de Jong","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"Pellegrino\u2010Coppola","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1062-5576","authenticated-orcid":false,"given":"Gerhard","family":"Burger","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Wink","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bob","family":"van de Water","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,13]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916\u2010016\u20100553\u20102"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2018.01.006"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2017.1341489"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4309"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-022-03266-6"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2018.07.017"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-021-06674-6"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kft232"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/tpj.2017.17"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-016-1781-0"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-018-2178-z"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-019-02552-0"},{"key":"e_1_2_12_14_1","first-page":"18.10.1","volume-title":"Current Protocols in Cell Biology","author":"Puigvert JC","year":"2010"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2017.00168"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-021-03141-w"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20110162"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.0c00296"},{"key":"e_1_2_12_20_1","first-page":"133","volume-title":"Advanced in Pharmacology","author":"Uetrecht J","year":"2019"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10030390"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104609"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-801238-3.11535-1"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-020-02792-5"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.018"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx4004038"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106094"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7677-5_24"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0048-x"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2021.114591"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2015-1255"},{"key":"e_1_2_12_32_1","first-page":"1","article-title":"Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation","volume":"1","author":"Stel W","year":"2021","journal-title":"Arch Toxicol"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf0971"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.11.007"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201702058"},{"key":"e_1_2_12_36_1","first-page":"1","article-title":"Integrated stress response of vertebrates is regulated by four eIF2\u03b1 kinases","volume":"6","author":"Taniuchi S","year":"2016","journal-title":"Sci Reports"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx1000865"},{"key":"e_1_2_12_38_1","first-page":"207","article-title":"Application of high\u2010throughput transcriptomics for mechanism\u2010based biological read\u2010across of short\u2010chain carboxylic acid analogues of valproic acid","volume":"39","author":"Vrijenhoek NG","year":"2022","journal-title":"ALTEX"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2003.11.007"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfz031"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/FAD.0b013e32831844cb"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.5b00465"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1044744"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/41.3.387"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11596-014-1296-y"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc11441"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2013.04.001"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.15822","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/liv.15822","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.15822","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:40Z","timestamp":1773014440000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.15822"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,13]]},"references-count":46,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["10.1111\/liv.15822"],"URL":"https:\/\/doi.org\/10.1111\/liv.15822","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,13]]},"assertion":[{"value":"2023-04-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}