{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T12:03:05Z","timestamp":1778328185814,"version":"3.51.4"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T00:00:00Z","timestamp":1650326400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Receptor\u2010interaction protein kinase 3 (RIP3), a critical determinant of the necroptotic pathway of programmed cell death, contributes to injury in murine models of alcohol\u2010associated liver disease (ALD); however, the underlying mechanisms are unknown. We investigated the effect of chronic ethanol feeding on the hepatic phosphoproteome in C57BL\/6 and RIP3\u2010deficient (<jats:italic toggle=\"yes\">Rip3<\/jats:italic>\n                           <jats:sup>\u2212\/\u2212<\/jats:sup>) mice, focusing on death receptor (DR) signaling pathways. C57BL\/6 and\u00a0<jats:italic toggle=\"yes\">Rip3<\/jats:italic>\n                           <jats:sup>\u2212\/\u2212<\/jats:sup> mice were fed an ethanol\u2010containing liquid diet or pair\u2010fed control diet. A label\u2010free mass spectrometry\u2010based approach identified differentially phosphorylated proteins that were mapped to pathways affected by ethanol and <jats:italic toggle=\"yes\">Rip3<\/jats:italic> genotype. Identified targets were validated in both the murine model of ALD and in liver tissue from patients with alcohol\u2010associated hepatitis (AH) and healthy controls. Chronic ethanol dysregulated hepatic tumor necrosis factor\u2010induced DR signaling pathways. Of particular importance, chronic ethanol feeding to C57BL\/6 mice decreased the phosphorylation of apoptosis signal\u2010regulating kinase 1 (ASK1) at serine (S)1036\/S1040 (S1029\/S1033 human), sites linked with the inhibition of ASK1 death\u2010promoting activity. This decrease in phosphorylation of inhibitory sites was muted in <jats:italic toggle=\"yes\">Rip3<\/jats:italic>\n                           <jats:sup>\u2212\/\u2212<\/jats:sup> mice. Decreased phosphorylation at S1033 was also lower in liver of patients with severe AH compared to healthy controls, and phosphorylation at the ASK1 activation site (threonine [Thr]\u2010838) was increased in patients with AH. The net impact of these changes in phosphorylation of ASK1 was associated with increased phosphorylation of p38, a downstream target of ASK1, in patients with AH and C57BL\/6 but not <jats:italic toggle=\"yes\">Rip3<\/jats:italic>\n                           <jats:sup>\u2212\/\u2212<\/jats:sup> mice. Similarly, chronic ethanol feeding affected the c\u2010Jun N\u2010terminal kinase pathway in C57BL\/6 but not <jats:italic toggle=\"yes\">Rip3<\/jats:italic>\n                           <jats:sup>\u2212\/\u2212<\/jats:sup> mice. Taken together, our data indicate that changes in inhibitory phosphorylation of ASK1 are an important target in ALD and suggest the involvement of noncanonical functions of\u00a0<jats:italic toggle=\"yes\">Rip3<\/jats:italic>\u00a0in ALD.<\/jats:p>","DOI":"10.1002\/hep4.1956","type":"journal-article","created":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T10:05:27Z","timestamp":1650362727000},"page":"2022-2041","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":13,"title":["Phosphoproteomics identifies pathways underlying the role of receptor\u2010interaction protein kinase 3 in alcohol\u2010associated liver disease and uncovers apoptosis signal\u2010regulating kinase 1 as a target"],"prefix":"10.1097","volume":"6","author":[{"given":"Vaibhav","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Inflammation and Immunity, Northern Ohio Alcohol Center, Center for Liver Disease Research,Cleveland Clinic,Lerner Research Institute,Cleveland,Ohio,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Northern Ohio Alcohol Center, Center for Liver Disease Research,Cleveland Clinic,Lerner Research Institute,Cleveland,Ohio,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vai","family":"Pathak","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences,Cleveland Clinic,Lerner Research Institute,Cleveland,Ohio,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Belinda B.","family":"Willard","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Core,Cleveland Clinic,Lerner Research Institute,Cleveland,Ohio,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela S.","family":"Allende","sequence":"additional","affiliation":[{"name":"2569,Department of Pathology,Cleveland Clinic,Cleveland,Ohio,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura E.","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Northern Ohio Alcohol Center, Center for Liver Disease Research,Cleveland Clinic,Lerner Research Institute,Cleveland,Ohio,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2022,4,19]]},"reference":[{"key":"hep41956-bib-0001-20241129","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.jhep.2018.10.023","article-title":"Inflammatory pathways in alcoholic steatohepatitis","volume":"70","year":"2019","journal-title":"J Hepatol"},{"key":"hep41956-bib-0002-20241129","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1053\/j.gastro.2016.02.035","article-title":"Linking pathogenic mechanisms of alcoholic liver disease with clinical 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