{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:06:33Z","timestamp":1791288393809,"version":"4.3.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"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":[[2019,7]]},"abstract":"<jats:p>\n                    Spermidine (SPD), a naturally occurring polyamine, has been recognized as a caloric restriction mimetic that confers health benefits, presumably by inducing autophagy. Recent studies have reported that oral administration of SPD protects against liver fibrosis and hepatocarcinogenesis through activation of microtubule associated protein 1S (MAP1S)\u2013mediated autophagy. Nuclear factor (erythroid\u2010derived 2)\u2010like 2 (NRF2) is a transcription factor that mediates cellular protection by maintaining the cell's redox, metabolic, and proteostatic balance. In this study, we demonstrate that SPD is a noncanonical NRF2 inducer, and that MAP1S is a component of this noncanonical pathway of NRF2 activation. Mechanistically, MAP1S induces NRF2 signaling through two parallel mechanisms, both resulting in NRF2 stabilization: (1) MAP1S competes with Kelch\u2010like ECH\u2010associated protein 1 (KEAP1) for NRF2 binding through an ETGE motif, and (2) MAP1S accelerates p62\u2010dependent degradation of KEAP1 by the autophagy pathway. We further demonstrate that SPD confers liver protection by enhancing NRF2 signaling. The importance of both NRF2 and p62\u2010dependent autophagy in SPD\u2010mediated liver protection was confirmed using a carbon tetrachloride\u2013induced liver fibrosis model in wild\u2010type,\n                    <jats:italic toggle=\"yes\">Nrf2\u2010\/\u2010<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">p62\u2010\/\u2010<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Nrf2\u2010\/\u2010;p62\u2010\/\u2010<\/jats:italic>\n                    mice, as the protective effect of SPD was significantly reduced in NRF2 or p62 single knockout mice, and completely abolished in the double knockout mice.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : Our results demonstrate the pivotal role of NRF2 in mediating the health benefit of SPD, particularly in the context of liver pathologies.\n                  <\/jats:p>","DOI":"10.1002\/hep.30616","type":"journal-article","created":{"date-parts":[[2019,3,15]],"date-time":"2019-03-15T04:22:49Z","timestamp":1552623769000},"page":"372-388","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":78,"title":["Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S\u2010Mediated Noncanonical Mechanism"],"prefix":"10.1097","volume":"70","author":[{"given":"Pengfei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy,University of Arizona,Tucson,AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat Rojo","family":"de la Vega","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy,University of Arizona,Tucson,AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Dodson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy,University of Arizona,Tucson,AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yue","sequence":"additional","affiliation":[{"name":"Center for Translational Cancer Research, Institute of Biosciences and Technology,Texas A&M University,Houston,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyun","family":"Shi","sequence":"additional","affiliation":[{"name":"Center for Translational Cancer Research, Institute of Biosciences and Technology,Texas A&M University,Houston,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyu","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pathology,Northwestern University Feinberg School of Medicine,Chicago,IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Chapman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy,University of Arizona,Tucson,AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Translational Cancer Research, Institute of Biosciences and Technology,Texas A&M University,Houston,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna D.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy,University of Arizona,Tucson,AZ"},{"name":"The University of Arizona Cancer Center,University of Arizona,Tucson,AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,5,20]]},"reference":[{"key":"hep30616-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1002\/hep.24515","article-title":"Biomarkers of liver fibrosis: What lies beneath the receiver operating characteristic curve?","volume":"54","year":"2011","journal-title":"Hepatology"},{"key":"hep30616-bib-0002-20241017","first-page":"961","article-title":"Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol","volume":"1","year":"2009","journal-title":"Aging (Albany NY)"},{"key":"hep30616-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1038\/nm.4222","article-title":"Cardioprotection and lifespan extension by the natural polyamine spermidine","volume":"22","year":"2016","journal-title":"Nat Med"},{"key":"hep30616-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.bbrc.2018.09.078","article-title":"Spermidine ameliorates non\u2010alcoholic fatty liver disease through regulating lipid metabolism via AMPK","volume":"505","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"hep30616-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"G899","DOI":"10.1152\/ajpgi.90507.2008","article-title":"Spermidine\/spermine\u2010N1\u2010acetyltransferase ablation protects against liver and kidney ischemia\u2010reperfusion injury in mice","volume":"296","year":"2009","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep30616-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1002\/lt.24471","article-title":"Oral administration of polyamines ameliorates liver ischemia\/reperfusion injury and promotes liver regeneration in rats","volume":"22","year":"2016","journal-title":"Liver Transpl"},{"key":"hep30616-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1158\/0008-5472.CAN-16-3462","article-title":"Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S\u2010mediated autophagy","volume":"77","year":"2017","journal-title":"Cancer Res"},{"key":"hep30616-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1074\/jbc.M408984200","article-title":"Microtubule\u2010associated protein 1S, a short and ubiquitously expressed member of the microtubule\u2010associated protein 1 family","volume":"280","year":"2005","journal-title":"J Biol Chem"},{"key":"hep30616-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"10367","DOI":"10.1074\/jbc.M110.206532","article-title":"Microtubule\u2010associated protein 1S (MAP1S) bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation","volume":"286","year":"2011","journal-title":"J Biol Chem"},{"key":"hep30616-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1095\/biolreprod.103.018531","article-title":"Identification and characterization of human VCY2\u2010interacting protein: VCY2IP\u20101, a microtubule\u2010associated protein\u2010like protein","volume":"70","year":"2004","journal-title":"Biol Reprod"},{"key":"hep30616-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1042\/BJ20130306","article-title":"Mitochondrion\u2010associated protein LRPPRC suppresses the initiation of basal levels of autophagy via enhancing Bcl\u20102 stability","volume":"454","year":"2013","journal-title":"Biochem J"},{"key":"hep30616-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: renovation of cells and tissues","volume":"147","year":"2011","journal-title":"Cell"},{"key":"hep30616-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"7537","DOI":"10.1158\/0008-5472.CAN-11-2170","article-title":"Autophagy enhanced by microtubule\u2010 and mitochondrion\u2010associated MAP1S suppresses genome instability and hepatocarcinogenesis","volume":"71","year":"2011","journal-title":"Cancer Res"},{"key":"hep30616-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"6255","DOI":"10.18632\/oncotarget.6669","article-title":"Fast clearance of lipid droplets through MAP1S\u2010activated autophagy suppresses clear cell renal cell carcinomas and promotes patient survival","volume":"7","year":"2016","journal-title":"Oncotarget"},{"key":"hep30616-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1002\/mc.22193","article-title":"Autophagy defects suggested by low levels of autophagy activator MAP1S and high levels of autophagy inhibitor LRPPRC predict poor prognosis of prostate cancer patients","volume":"54","year":"2015","journal-title":"Mol Carcinog"},{"key":"hep30616-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1101\/gad.225680.113","article-title":"The emerging role of the Nrf2\u2013Keap1 signaling pathway in cancer","volume":"27","year":"2013","journal-title":"Genes Dev"},{"key":"hep30616-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev.pharmtox.46.120604.141046","article-title":"Cell survival responses to environmental stresses via the Keap1\u2010Nrf2\u2010ARE pathway","volume":"47","year":"2007","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"hep30616-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1146\/annurev-pharmtox-010818-021856","article-title":"Modulating NRF2 in disease: timing is everything","volume":"59","year":"2019","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"hep30616-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1101\/gad.13.1.76","article-title":"Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino\u2010terminal Neh2 domain","volume":"13","year":"1999","journal-title":"Genes Dev"},{"key":"hep30616-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"10941","DOI":"10.1128\/MCB.24.24.10941-10953.2004","article-title":"Keap1 is a redox\u2010regulated substrate adaptor protein for a Cul3\u2010dependent ubiquitin ligase complex","volume":"24","year":"2004","journal-title":"Mol Cell Biol"},{"key":"hep30616-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1089\/ars.2010.3211","article-title":"Regulation of the Nrf2\u2010Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin\u2010ring ubiquitin ligases","volume":"13","year":"2010","journal-title":"Antioxid Redox Signal"},{"key":"hep30616-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"2887","DOI":"10.1128\/MCB.26.8.2887-2900.2006","article-title":"Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two\u2010site molecular recognition model","volume":"26","year":"2006","journal-title":"Mol Cell Biol"},{"key":"hep30616-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"24756","DOI":"10.1074\/jbc.M601119200","article-title":"Dimerization of substrate adaptors can facilitate cullin\u2010mediated ubiquitylation of proteins by a \u201ctethering\u201d mechanism: a two\u2010site interaction model for the Nrf2\u2010Keap1 complex","volume":"281","year":"2006","journal-title":"J Biol Chem"},{"key":"hep30616-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"15259","DOI":"10.1073\/pnas.1305687110","article-title":"Regulatory flexibility in the Nrf2\u2010mediated stress response is conferred by conformational cycling of the Keap1\u2010Nrf2 protein complex","volume":"110","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep30616-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"16782","DOI":"10.1074\/jbc.M109.096545","article-title":"Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1\u2010Nrf2 cell defense pathway","volume":"285","year":"2010","journal-title":"J Biol Chem"},{"key":"hep30616-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"3275","DOI":"10.1128\/MCB.00248-10","article-title":"A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62","volume":"30","year":"2010","journal-title":"Mol Cell Biol"},{"key":"hep30616-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/ncb2021","article-title":"The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1","volume":"12","year":"2010","journal-title":"Nat Cell Biol"},{"key":"hep30616-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.phrs.2012.07.004","article-title":"p62\/SQSTM1\/A170: physiology and pathology","volume":"66","year":"2012","journal-title":"Pharmacol Res"},{"key":"hep30616-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1089\/ars.2011.4394","article-title":"p62 at the interface of autophagy, oxidative stress signaling, and cancer","volume":"17","year":"2012","journal-title":"Antioxid Redox Signal"},{"key":"hep30616-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1128\/MCB.01748-12","article-title":"Arsenic inhibits autophagic flux, activating the Nrf2\u2010Keap1 pathway in a p62\u2010dependent manner","volume":"33","year":"2013","journal-title":"Mol Cell Biol"},{"key":"hep30616-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.freeradbiomed.2015.06.007","article-title":"The antioxidant function of sestrins is mediated by promotion of autophagic degradation of Keap1 and Nrf2 activation and by inhibition of mTORC1","volume":"88","year":"2015","journal-title":"Free Radic Biol Med"},{"key":"hep30616-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1089\/ars.2017.7356","article-title":"The regulation of NRF2 by nutrient\u2010responsive signaling and its role in anabolic cancer metabolism","volume":"29","year":"2018","journal-title":"Antioxid Redox Signal"},{"key":"hep30616-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1080\/15548627.2017.1356550","article-title":"Lipopolysaccharide mediates hepatic stellate cell activation by regulating autophagy and retinoic acid signaling","volume":"13","year":"2017","journal-title":"Autophagy"},{"key":"hep30616-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR\u2010Cas9 system","volume":"8","year":"2013","journal-title":"Nat Protoc"},{"key":"hep30616-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"6334","DOI":"10.1128\/MCB.00630-07","article-title":"Keap1 controls postinduction repression of the Nrf2\u2010mediated antioxidant response by escorting nuclear export of Nrf2","volume":"27","year":"2007","journal-title":"Mol Cell Biol"},{"key":"hep30616-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1101\/gad.238246.114","article-title":"Hrd1 suppresses Nrf2\u2010mediated cellular protection during liver cirrhosis","volume":"28","year":"2014","journal-title":"Genes Dev"},{"key":"hep30616-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"13943","DOI":"10.1073\/pnas.93.24.13943","article-title":"NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development","volume":"93","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep30616-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/j.1872-034X.2008.00478.x","article-title":"The alpha\u2010glucosidase inhibitor acarbose prevents obesity and simple steatosis in sequestosome 1\/A170\/p62 deficient mice","volume":"39","year":"2009","journal-title":"Hepatol Res"},{"key":"hep30616-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"12637","DOI":"10.18632\/oncotarget.14478","article-title":"Augmenter of liver regeneration protects against carbon tetrachloride\u2010induced liver injury by promoting autophagy in mice","volume":"8","year":"2017","journal-title":"Oncotarget"},{"key":"hep30616-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/jpi.12247","article-title":"Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride\u2010induced fibrosis","volume":"59","year":"2015","journal-title":"J Pineal Res"},{"key":"hep30616-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1053\/hupa.2000.8440","article-title":"Hepatic stellate cell activation in nonalcoholic steatohepatitis and fatty liver","volume":"31","year":"2000","journal-title":"Hum Pathol"},{"key":"hep30616-bib-0042-20241017","article-title":"Spermidine in health and disease","volume":"359","year":"2018","journal-title":"Science"},{"key":"hep30616-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"5572","DOI":"10.3402\/fnr.v55i0.5572","article-title":"Polyamines in foods: development of a food database","volume":"55","year":"2011","journal-title":"Food Nutr Res"},{"key":"hep30616-bib-0044-20241017","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1161\/CIRCRESAHA.117.310603","article-title":"Spermidine promotes cardioprotective autophagy","volume":"120","year":"2017","journal-title":"Circ Res"},{"key":"hep30616-bib-0045-20241017","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1093\/toxsci\/kfs133","article-title":"Liver\u2010specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen\u2010induced liver injury","volume":"127","year":"2012","journal-title":"Toxicol Sci"},{"key":"hep30616-bib-0046-20241017","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.molcel.2013.08.003","article-title":"Phosphorylation of p62 activates the Keap1\u2010Nrf2 pathway during selective autophagy","volume":"51","year":"2013","journal-title":"Mol Cell"},{"key":"hep30616-bib-0047-20241017","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.bbrc.2005.05.006","article-title":"Putative tumor suppressor RASSF1 interactive protein and cell death inducer C19ORF5 is a DNA binding protein","volume":"332","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"hep30616-bib-0048-20241017","doi-asserted-by":"crossref","first-page":"8606","DOI":"10.1038\/s41598-018-26611-1","article-title":"Pomegranate action in curbing the incidence of liver injury triggered by Diethylnitrosamine by declining oxidative stress via Nrf2 and NFkappaB regulation","volume":"8","year":"2018","journal-title":"Sci Rep"},{"key":"hep30616-bib-0049-20241017","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1038\/aps.2014.41","article-title":"Nrf2 pathway activation contributes to anti\u2010fibrosis effects of ginsenoside Rg1 in a rat model of alcohol\u2010 and CCl4\u2010induced hepatic fibrosis","volume":"35","year":"2014","journal-title":"Acta Pharmacol Sin"},{"key":"hep30616-bib-0050-20241017","article-title":"Aldehyde dehydrogenase 2 activation ameliorates CCl4\u2010induced chronic liver fibrosis in mice by up\u2010regulating Nrf2\/HO\u20101 antioxidant pathway","year":"2018","journal-title":"J Cell Mol Med"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.30616","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.30616","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201907000-00029","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T20:47:04Z","timestamp":1729198024000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201907000-00029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,20]]},"references-count":50,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.30616","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,20]]},"assertion":[{"value":"2019-01-13","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-12","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}