{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:37:12Z","timestamp":1789468632850,"version":"build-2803163510"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"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":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism\u2010associated signaling pathways. However, the role of OTUB1 in NASH is unclarified.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p>We demonstrated that mice with <jats:italic toggle=\"yes\">Otub1<\/jats:italic> deficiency exhibited aggravated high\u2010fat diet\u2013induced and high\u2010fat high\u2010cholesterol (HFHC) diet\u2013induced hyperinsulinemia and liver steatosis. Notably, hepatocyte\u2010specific overexpression of <jats:italic toggle=\"yes\">Otub1<\/jats:italic> markedly alleviated HFHC diet\u2013induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal\u2013regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA\u2010sequencing analysis and immunoblot analysis. Through immunoprecipitation\u2013mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor\u2013associated factor 6 (TRAF6) and suppressed its lysine 63\u2013linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6\u2010mediated ASK1 activation. Targeting the OTUB1\u2010TRAF6\u2010ASK1 axis may be a promising therapeutic strategy for NASH.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32179","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T15:57:17Z","timestamp":1633017437000},"page":"1218-1234","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":42,"title":["OTUB1 alleviates NASH through inhibition of the TRAF6\u2010ASK1 signaling pathways"],"prefix":"10.1097","volume":"75","author":[{"given":"Jie\u2010Lei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrinology,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin\u2010Bin","family":"Du","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dian\u2010Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Li","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling\u2010Yao","family":"Kong","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang\u2010Jian","family":"Fan","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases, Institute 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University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u2010Lu","family":"Yang","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng\u2010Yang","family":"Hao","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei\u2010Ming","family":"Wu","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Huang","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2010Zeng","family":"Dong","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Yao","sequence":"additional","affiliation":[{"name":"Cardiovascular Hospital,the First 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