{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:04:08Z","timestamp":1790701448323,"version":"4.1.0"},"reference-count":57,"publisher":"National Academy of Sciences","issue":"40","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["DK135538"],"award-info":[{"award-number":["DK135538"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["ES030429"],"award-info":[{"award-number":["ES030429"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["DK145468"],"award-info":[{"award-number":["DK145468"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:p>\n                    Protein\n                    <jats:italic toggle=\"yes\">S<\/jats:italic>\n                    -sulfinylation is a reversible oxidative cysteine modification, but its contribution to acute liver injury such as those induced by acetaminophen (APAP) overdose has not been reported. Sulfiredoxin-1 (SRXN1) is the only oxidoreductase known to reduce the sulfinylated proteins, yet the substrates and mechanisms through which it protects against acute liver injury are unclear. Here, we show that hepatic protein\n                    <jats:italic toggle=\"yes\">S<\/jats:italic>\n                    -sulfinylation was markedly upregulated in APAP-overdose patients and mice. Hepatocyte-specific knockout or pharmacological inhibition of\n                    <jats:italic toggle=\"yes\">Srxn1<\/jats:italic>\n                    sensitized mice to APAP-induced acute liver injury. In contrast, overexpression of SRXN1, but not its oxidoreductase-dead C99S mutant, protected mice from APAP-induced liver injury. Mechanistically, we identified the deubiquitinase ubiquitin-specific protease 7 (USP7) as an SRXN1 substrate required for hepatoprotection. USP7 inhibition worsened APAP-induced liver injury, whereas its overexpression alleviated injury by stabilizing its deubiquitinase substrate heme oxygenase-1 (HO-1). Loss of SRXN1 enhanced\n                    <jats:italic toggle=\"yes\">S<\/jats:italic>\n                    -sulfinylation of USP7 at Cys315, promoting its ubiquitination and degradation. SRXN1 expression correlated with USP7 levels in human liver samples. Delayed lipid nanoparticle (LNP) delivery of SRXN1 messenger RNA (mRNA) mitigated established APAP-induced liver injury beyond the therapeutic window of\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -acetylcysteine. These findings define an SRXN1-USP7-HO-1 axis as a promising therapeutic target for oxidative liver injury and highlight LNP-mediated SRXN1 mRNA delivery as a potential treatment approach.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2620180123","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:18:26Z","timestamp":1790698706000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Desulfinylation of the deubiquitinase USP7 by SRXN1 attenuates oxidative acute liver injury"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2534-9669","authenticated-orcid":false,"given":"Mengyun","family":"Ke","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Won","family":"Kim","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meishu","family":"Xu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyi","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syamprasad","family":"N. 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Yoon, A. Babar, M. Choudhary, M. Kutner, N. Pyrsopoulos, Acetaminophen-induced hepatotoxicity: A comprehensive update. J. Clin. Transl. Hepatol. 4, 131\u2013142 (2016).","journal-title":"J. Clin. Transl. 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Wang , Ulinastatin protects against acetaminophen-induced liver injury by alleviating ferroptosis via the SIRT1\/NRF2\/HO-1 pathway. Am. J. Transl. Res. 13, 6031\u20136042 (2021).","journal-title":"Am. J. Transl. Res."},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.06.031"},{"key":"e_1_3_4_55_2","unstructured":"T. G. Bird Transcriptional analysis of in vivo responses to acetaminophen induced hepatic injury in the murine liver. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE111828. Deposited 14 March 2018."},{"key":"e_1_3_4_56_2","unstructured":"Q. Cui L. Xiao N. Wang Protein S-nitrosylation restricts xenobiotic receptor PXR hyperactivity and ameliorates acetaminophen-induced liver injury in mice. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE243679. Deposited 20 September 2023."},{"key":"e_1_3_4_57_2","unstructured":"A. O. Pisco N. Schaum S. Darmanis T. Wyss-Coray S. R. Quake Tabula muris senis. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE149590. Deposited 29 April 2020."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2620180123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:19:05Z","timestamp":1790698745000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2620180123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":57,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2026,10,6]]}},"alternative-id":["10.1073\/pnas.2620180123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2620180123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"assertion":[{"value":"2026-06-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2620180123"}}