{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T13:23:09Z","timestamp":1790342589362,"version":"4.1.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2019,6,22]],"date-time":"2019-06-22T00:00:00Z","timestamp":1561161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,6,22]],"date-time":"2019-06-22T00:00:00Z","timestamp":1561161600000},"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":[[2019,11]]},"abstract":"<jats:p>Hepatic ischemia\u2010reperfusion (IR) injury is the leading cause of liver dysfunction and failure after liver resection or transplantation and lacks effective therapeutic strategies. Here, we applied a systematic proteomic analysis to identify the prominent contributors to IR\u2010induced liver damage and promising therapeutic targets for this condition. Based on an unbiased proteomic analysis, we found that toll\u2010interacting protein (Tollip) expression was closely correlated with the hepatic IR process. RNA sequencing analysis and phenotypic examination showed a dramatically alleviated hepatic IR injury by <jats:italic toggle=\"yes\">Tollip<\/jats:italic> deficiency both <jats:italic toggle=\"yes\">in vivo<\/jats:italic> and in hepatocytes. Mechanistically, Tollip interacts with apoptosis signal\u2010regulating kinase 1 (ASK1) and facilitates the recruitment of tumor necrosis factor receptor\u2013associated factor 6 (TRAF6) to ASK1, leading to enhanced ASK1 N\u2010terminal dimerization and the subsequent activation of downstream mitogen\u2010activated protein kinase (MAPK) signaling. Furthermore, the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for Tollip\u2010regulated ASK1\u2013MAPK axis activation. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Tollip is a regulator of hepatic IR injury by facilitating ASK1 N\u2010terminal dimerization and the resultant c\u2010Jun N\u2010terminal kinase\/p38 signaling activation. Inhibiting Tollip or its interaction with ASK1 might be promising therapeutic strategies for hepatic IR injury.<\/jats:p>","DOI":"10.1002\/hep.30705","type":"journal-article","created":{"date-parts":[[2019,5,11]],"date-time":"2019-05-11T14:13:08Z","timestamp":1557583988000},"page":"1750-1769","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":55,"title":["Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia\u2010Reperfusion Injury in Mice"],"prefix":"10.1097","volume":"70","author":[{"given":"Zhen\u2010Zhen","family":"Yan","sequence":"first","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong\u2010Ping","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai\u2010Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan University,Wuhan,China"},{"name":"Basic Medical School,Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Ren","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui\u2010Feng","family":"Tian","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Cheng","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan University,Wuhan,China"},{"name":"Medical Science Research Center,Zhongnan Hospital of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Cai","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010Yong","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi\u2010Gang","family":"She","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zan","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan 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