{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:55:38Z","timestamp":1787849738774,"version":"build-2784847793"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T00:00:00Z","timestamp":1612569600000},"content-version":"vor","delay-in-days":36,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Protein S\u2010sulfhydration mediated by H<jats:sub>2<\/jats:sub>S has been shown to play important roles in several diseases. However, its precise role in liver disease and the related mechanism remain unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We showed that in streptozotocin (STZ)\u2013treated and high\u2010fat diet (HFD)\u2013treated low\u2010density lipoprotein receptor\u2013negative (LDLr<jats:sup>\u2212\/\u2212<\/jats:sup>) mice, the H<jats:sub>2<\/jats:sub>S donor GYY4137 ameliorated liver injury, decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, mitigated lipid deposition, and reduced hepatocyte death. Strikingly, S\u2010sulfhydration of Kelch\u2010like ECH\u2010associated protein 1 (Keap1) was decreased in the livers of patients with fatty liver under diabetic conditions. In STZ+HFD\u2010treated LDLr<jats:sup>\u2212\/\u2212<\/jats:sup> mice and in high glucose\u2013treated and oxidized low\u2010density lipoprotein (ox\u2010LDL)\u2013treated primary mouse hepatocytes, the GYY4137\u2010mediated increase in Keap1 S\u2010sulfhydration induced nuclear erythroid 2\u2010related factor 2 (Nrf2) dissociation from Keap1, which enhanced the nuclear translocation of Nrf2 itself and the consequent expression of antioxidant proteins. Keap1 Cys151 mutation significantly reduced Keap1 S\u2010sulfhydration and abolished the hepatoprotective effects of H<jats:sub>2<\/jats:sub>S both <jats:italic toggle=\"yes\">in vivo<\/jats:italic> and <jats:italic toggle=\"yes\">in vitro<\/jats:italic>. Nrf2 deficiency inhibited the H<jats:sub>2<\/jats:sub>S\u2010induced beneficial impacts in Nrf2<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Similarly, in CCl<jats:sub>4<\/jats:sub>\u2010stimulated mice, GYY4137 increased Keap1 S\u2010sulfhydration, improved liver function, alleviated liver fibrosis, decreased hepatic oxidative stress, and activated the Nrf2 signaling pathway; and these effects were abrogated after Keap1 Cys151 mutation. Moreover, H<jats:sub>2<\/jats:sub>S increased the binding of Nrf2 to the promoter region of LDLr\u2010related protein 1 (<jats:italic toggle=\"yes\">Lrp1<\/jats:italic>) and consequently up\u2010regulated LRP1 expression, but these effects were disrupted by Keap1 Cys151 mutation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>H<jats:sub>2<\/jats:sub>S\u2010mediated Keap1 S\u2010sulfhydration alleviates liver damage through activation of Nrf2. Hence, administration of exogenous H<jats:sub>2<\/jats:sub>S in the form of the H<jats:sub>2<\/jats:sub>S donor GYY4137 may be of therapeutic benefit in the context of concurrent hyperlipidemia and hyperglycemia\u2013induced or CCl<jats:sub>4<\/jats:sub>\u2010stimulated liver dysfunction.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31247","type":"journal-article","created":{"date-parts":[[2020,3,27]],"date-time":"2020-03-27T04:53:01Z","timestamp":1585284781000},"page":"282-302","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":104,"title":["Hydrogen Sulfide Alleviates Liver Injury Through the S\u2010Sulfhydrated\u2010Kelch\u2010Like ECH\u2010Associated Protein 1\/Nuclear Erythroid 2\u2013Related Factor 2\/Low\u2010Density Lipoprotein Receptor\u2013Related Protein 1 Pathway"],"prefix":"10.1097","volume":"73","author":[{"given":"Shuang","family":"Zhao","sequence":"first","affiliation":[{"name":"Key Laboratory of 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University,Nanjing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyi","family":"Cao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Targeted Intervention of Cardiovascular Disease,Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,Nanjing Medical University,Nanjing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Miao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Targeted Intervention of Cardiovascular Disease,Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,Nanjing Medical University,Nanjing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular and Cerebrovascular Medicine,Nanjing Medical 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