{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T11:25:31Z","timestamp":1764588331523,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:00:00Z","timestamp":1661299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Project of Innovation Research 2035 Pilot Plan of Southwest University","award":["SWU-XDZD22007","SWU116068","cstc2018jcyjAX0401","cx2018083"],"award-info":[{"award-number":["SWU-XDZD22007","SWU116068","cstc2018jcyjAX0401","cx2018083"]}]},{"DOI":"10.13039\/501100006250","name":"Hundred Talents Plan of Chongqing and Southwest University \u2018Gathering Talent Project\u2019","doi-asserted-by":"publisher","award":["SWU-XDZD22007","SWU116068","cstc2018jcyjAX0401","cx2018083"],"award-info":[{"award-number":["SWU-XDZD22007","SWU116068","cstc2018jcyjAX0401","cx2018083"]}],"id":[{"id":"10.13039\/501100006250","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing","doi-asserted-by":"publisher","award":["SWU-XDZD22007","SWU116068","cstc2018jcyjAX0401","cx2018083"],"award-info":[{"award-number":["SWU-XDZD22007","SWU116068","cstc2018jcyjAX0401","cx2018083"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chongqing Innovation and Entrepreneurship Program for Overseas Returnee","award":["SWU-XDZD22007","SWU116068","cstc2018jcyjAX0401","cx2018083"],"award-info":[{"award-number":["SWU-XDZD22007","SWU116068","cstc2018jcyjAX0401","cx2018083"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Acetaminophen (APAP) is one of the most widely used drugs with antipyretic and analgesic effects, and thus hepatotoxicity from the overdose of APAP becomes one of the most common forms of drug-induced liver injury. The reaction towards thiol molecules, such as GSH by APAP metabolite, N-acetyl-p-benzo-quinonimine (NAPQI), is the main cause of APAP-induced hepatotoxicity. However, the role of many other thiol-related regulators in toxicity caused by APAP is still unclear. Here we have found that knockout of the Glrx2 gene, which encodes mitochondrial glutaredoxin2 (Grx2), sensitized mice to APAP-caused hepatotoxicity. Glrx2 deletion hindered Nrf2-mediated compensatory recovery of thiol-dependent redox systems after acetaminophen challenge, resulting in a more oxidized cellular state with a further decrease in GSH level, thioredoxin reductase activity, and GSH\/GSSG ratio. The weakened feedback regulation capacity of the liver led to higher levels of protein glutathionylation and thioredoxin (both Trx1 and Trx2) oxidation in Glrx2\u2212\/\u2212 mice. Following the cellular environment oxidation, nuclear translocation of apoptosis-inducing factor (AIF) was elevated in the liver of Glrx2\u2212\/\u2212 mice. Taken together, these results demonstrated that mitochondrial Grx2 deficiency deteriorated APAP-induced hepatotoxicity by interrupting thiol-redox compensatory response, enhancing the AIF pathway-mediated oxidative damage.<\/jats:p>","DOI":"10.3390\/antiox11091643","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T21:03:51Z","timestamp":1661375031000},"page":"1643","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mitochondrial Glrx2 Knockout Augments Acetaminophen-Induced Hepatotoxicity in Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Jing","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education (Southwest University), College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China"},{"name":"West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuewen","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education (Southwest University), College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing","family":"Wen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education (Southwest University), College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5644-9008","authenticated-orcid":false,"given":"Xiaoyuan","family":"Ren","sequence":"additional","affiliation":[{"name":"Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huihui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"},{"name":"Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yatao","family":"Du","sequence":"additional","affiliation":[{"name":"Ministry of Education-Shanghai Key Laboratory of Children\u2019s Environmental Health, Institute of Early Life Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1699-8835","authenticated-orcid":false,"given":"Jun","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education (Southwest University), College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"878","DOI":"10.14309\/ajg.0000000000001259","article-title":"ACG clinical guideline: Diagnosis and management of idiosyncratic drug-induced liver injury","volume":"116","author":"Chalasani","year":"2021","journal-title":"Am. 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