{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:51:39Z","timestamp":1791305499926,"version":"4.3.1"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Insititutes of Health","award":["R01AA032010"],"award-info":[{"award-number":["R01AA032010"]}]},{"name":"National Institutes of Health","award":["R01AA026759"],"award-info":[{"award-number":["R01AA026759"]}]},{"name":"National Institutes of Health","award":["T32HL170963"],"award-info":[{"award-number":["T32HL170963"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities (MICIU) and the State Research Agency","award":["PID2023-146132OB-I00"],"award-info":[{"award-number":["PID2023-146132OB-I00"]}],"id":[{"id":"https:\/\/ror.org\/05r0vyz12","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Alcohol-associated liver disease (ALD) is associated with higher incidence of colorectal liver metastasis (CRLM); prohibitin 1 (PHB1) defends against CRLM yet its role in ALD and ALD-CRLM is poorly understood and was investigated here. In human, murine, and in vitro ALD models, cytosolic and nuclear PHB1 were depleted, whereas mitochondrial PHB1 was preserved despite a loss in mitochondrial mass. Nuclear PHB1 loss was driven by CRM1-mediated export, and blocking this interaction with a PHB1 nuclear export signal (NES) peptide retained nuclear PHB1, ameliorating both ALD and ALD-CRLM. PHB1 NES prevented depletion of nuclear methionine adenosyltransferase \u03b11, oxidative stress, and induction of matrix metalloproteinase 7 (MMP-7) and multiple oncogenes. Single-nucleus RNA sequencing of NIAAA diet-fed mouse livers and spatial transcriptomics of ALD-CRLM mice livers revealed that PHB1 NES treatment mitigated alcohol-induced metabolic and oncogenic stress, attenuated pro-inflammation and pro-fibrogenic responses, remodeled immunosuppressive microenvironment and contributed to overall hepatoprotection. These findings identify nuclear PHB1 depletion as a driver and a promising therapeutic target in ALD and ALD-CRLM.<\/jats:p>","DOI":"10.1172\/jci206235","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:00:31Z","timestamp":1791302431000},"source":"Crossref","is-referenced-by-count":0,"title":["Nuclear prohibitin 1 depletion drives alcohol-associated liver injury and sensitization to colon cancer liver metastasis"],"prefix":"10.1172","author":[{"given":"Jyoti","family":"Chhimwal","sequence":"first","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonal","family":"Sinha","sequence":"additional","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jina","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Alba","sequence":"additional","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Barbier-Torres","sequence":"additional","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaohong","family":"Wang","sequence":"additional","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heping","family":"Yang","sequence":"additional","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngyi","family":"Lim","sequence":"additional","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8384-2793","authenticated-orcid":true,"given":"Ramachandran","family":"Murali","sequence":"additional","affiliation":[{"name":"Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8156-9052","authenticated-orcid":true,"given":"Maria Lauda","family":"Tomasi","sequence":"additional","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3513-1783","authenticated-orcid":true,"given":"Sungyong","family":"You","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Mato","sequence":"additional","affiliation":[{"name":"CIC bioGUNE, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly C.","family":"Lu","sequence":"additional","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,10,6]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/206235\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:00:33Z","timestamp":1791302433000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/206235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,6]]},"references-count":0,"alternative-id":["10.1172\/JCI206235"],"URL":"https:\/\/doi.org\/10.1172\/jci206235","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,6]]}}}