{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T20:01:55Z","timestamp":1772481715484,"version":"3.50.1"},"reference-count":100,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,11,29]],"date-time":"2019-11-29T00:00:00Z","timestamp":1574985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pin1 is one of the three known prolyl-isomerase types and its hepatic expression level is markedly enhanced in the obese state. Pin1 plays critical roles in favoring the exacerbation of both lipid accumulation and fibrotic change accompanying inflammation. Indeed, Pin1-deficient mice are highly resistant to non-alcoholic steatohepatitis (NASH) development by either a high-fat diet or methionine\u2013choline-deficient diet feeding. The processes of NASH development can basically be separated into lipid accumulation and subsequent fibrotic change with inflammation. In this review, we outline the molecular mechanisms by which increased Pin1 promotes both of these phases of NASH. The target proteins of Pin1 involved in lipid accumulation include insulin receptor substrate 1 (IRS-1), AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase 1 (ACC1), while the p60 of the NF-kB complex and transforming growth factor \u03b2 (TGF-\u03b2) pathway appear to be involved in the fibrotic process accelerated by Pin1. Interestingly, Pin1 deficiency does not cause abnormalities in liver size, appearance or function. Therefore, we consider the inhibition of increased Pin1 to be a promising approach to treating NASH and preventing hepatic fibrosis.<\/jats:p>","DOI":"10.3390\/cells8121545","type":"journal-article","created":{"date-parts":[[2019,11,29]],"date-time":"2019-11-29T10:58:21Z","timestamp":1575025101000},"page":"1545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins"],"prefix":"10.3390","volume":"8","author":[{"given":"Masa-Ki","family":"Inoue","sequence":"first","affiliation":[{"name":"Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minamitnf-ku, Hiroshima City, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Nakatsu","sequence":"additional","affiliation":[{"name":"Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minamitnf-ku, Hiroshima City, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Yamamotoya","sequence":"additional","affiliation":[{"name":"Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minamitnf-ku, Hiroshima City, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shun","family":"Hasei","sequence":"additional","affiliation":[{"name":"Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minamitnf-ku, Hiroshima City, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayu","family":"Kanamoto","sequence":"additional","affiliation":[{"name":"Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minamitnf-ku, Hiroshima City, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miki","family":"Naitou","sequence":"additional","affiliation":[{"name":"Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minamitnf-ku, Hiroshima City, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuka","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Infection &amp; Inflammation, School of Medicine, Tulane University, 6823 St. Charles Avenue, New Orleans, LA 70118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyuki","family":"Sakoda","sequence":"additional","affiliation":[{"name":"Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Midori","family":"Fujishiro","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiraku","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akifumi","family":"Kushiyama","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy, Meiji Pharmaceutical University 2-522-1 Noshio Kiyose, Tokyo 204-8588, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoichiro","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minamitnf-ku, Hiroshima City, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s00535-010-0311-8","article-title":"Prevalence, gender, ethnic variations, and prognosis of NASH","volume":"46","author":"Hashimoto","year":"2011","journal-title":"J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1007\/s10620-016-4143-0","article-title":"Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations","volume":"61","author":"Sherif","year":"2016","journal-title":"Dig. Dis. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/j.1365-2036.2011.04724.x","article-title":"Systematic review: The epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults","volume":"34","author":"Vernon","year":"2011","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/hep.24127","article-title":"Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: Distinct clinicopathologic meanings","volume":"53","author":"Brunt","year":"2011","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1111\/j.1478-3231.2006.01311.x","article-title":"Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures","volume":"26","author":"Halpern","year":"2006","journal-title":"Liver Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/S0002-9343(03)00449-2","article-title":"Is weight reduction an effective therapy for nonalcoholic fatty liver? A systematic review","volume":"115","author":"Wang","year":"2003","journal-title":"Am. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/hep.23276","article-title":"Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis","volume":"51","author":"Promrat","year":"2010","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"722","DOI":"10.7326\/0003-4819-143-10-200511150-00009","article-title":"The metabolic syndrome as a predictor of nonalcoholic fatty liver disease","volume":"143","author":"Hamaguchi","year":"2005","journal-title":"Ann. Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S0002-9343(99)00271-5","article-title":"Association of nonalcoholic fatty liver disease with insulin resistance","volume":"107","author":"Marchesini","year":"1999","journal-title":"Am. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1097\/00004836-200609000-00016","article-title":"Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of taiwan: Metabolic significance of nonalcoholic fatty liver disease in nonobese adults","volume":"40","author":"Chen","year":"2006","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1136\/pgmj.2006.052258","article-title":"Prevalence and risk factors of fatty liver disease in the Shuiguohu district of Wuhan city, central China","volume":"83","author":"Wang","year":"2007","journal-title":"Postgrad. Med. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/j.1440-1746.2007.04892.x","article-title":"The importance of metabolic factors for the increasing prevalence of fatty liver in Shanghai factory workers","volume":"22","author":"Fan","year":"2007","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1111\/j.1600-6143.2009.02590.x","article-title":"Outcome after liver transplantation for NASH cirrhosis","volume":"9","author":"Malik","year":"2009","journal-title":"Am. J. Transplant."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/s41419-018-0844-y","article-title":"Prolyl isomerase Pin1: A promoter of cancer and a target for therapy","volume":"9","author":"Chen","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_16","first-page":"153","article-title":"Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions","volume":"22","author":"Pearson","year":"2001","journal-title":"Endocr. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1146\/annurev.cellbio.13.1.261","article-title":"Cyclin-dependent kinases: Engines, clocks, and microprocessors","volume":"13","author":"Morgan","year":"1997","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S0962-8924(02)02253-5","article-title":"Pinning down proline-directed phosphorylation signaling","volume":"12","author":"Lu","year":"2002","journal-title":"Trends Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1016\/j.bbagen.2014.12.019","article-title":"Control of protein function by prolyl isomerization","volume":"1850","author":"Schmidpeter","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1146\/annurev.bb.22.060193.001011","article-title":"Prolyl isomerase: Enzymatic catalysis of slow protein-folding reactions","volume":"22","author":"Schmid","year":"1993","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S377","DOI":"10.1046\/j.1440-1746.17.s3.31.x","article-title":"Non-alcoholic steatohepatitis: Definitions and pathogenesis","volume":"17","author":"Day","year":"2002","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nrc2107","article-title":"PIN1, the cell cycle and cancer","volume":"7","author":"Yeh","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/77929","article-title":"Structural basis for phosphoserine-proline recognition by group IV WW domains","volume":"7","author":"Verdecia","year":"2000","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1515\/hsz-2017-0137","article-title":"Structure and function of the human parvulins Pin1 and Par14\/17","volume":"399","author":"Matena","year":"2018","journal-title":"Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.jhep.2009.04.016","article-title":"The peptidyl-prolyl isomerase, Pin1, facilitates NF-kappaB binding in hepatocytes and protects against hepatic ischemia\/reperfusion injury","volume":"51","author":"Kuboki","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.jhep.2014.02.004","article-title":"Pin1 induction in the fibrotic liver and its roles in TGF-\u03b21 expression and Smad2\/3 phosphorylation","volume":"60","author":"Yang","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3459","DOI":"10.1093\/emboj\/20.13.3459","article-title":"Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1","volume":"20","author":"Wulf","year":"2001","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/ncb1822","article-title":"The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer","volume":"11","author":"Rustighi","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5219","DOI":"10.2174\/13816128113199990381","article-title":"Genetic Predisposition in NAFLD and NASH: Impact on Severity of Liver Disease and Response to Treatment","volume":"19","author":"Dongiovanni","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","article-title":"Steatohepatitis: A tale of two \u201chits\u201d?","volume":"114","author":"Day","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev-pathol-121808-102132","article-title":"Nonalcoholic fatty liver disease: Pathology and pathogenesis","volume":"5","author":"Tiniakos","year":"2010","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/hep.20283","article-title":"Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway","volume":"40","author":"Feldstein","year":"2004","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cmet.2006.07.006","article-title":"Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis","volume":"4","author":"Caballero","year":"2006","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44526","DOI":"10.1074\/jbc.M112.397133","article-title":"Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model","volume":"287","author":"Nakatsu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3221.e3","DOI":"10.1016\/j.celrep.2019.02.066","article-title":"Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16","volume":"26","author":"Nakatsu","year":"2019","journal-title":"Cell Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Nakatsu, Y., Matsunaga, Y., Yamamotoya, T., Ueda, K., Inoue, Y., Mori, K., Sakoda, H., Fujishiro, M., Ono, H., and Kushiyama, A. (2016). Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091495"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/nrm2066","article-title":"Adipocyte differentiation from the inside out","volume":"7","author":"Rosen","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1038\/onc.2009.98","article-title":"Peptidyl-prolyl cis\/trans isomerase Pin1 is critical for the regulation of PKB\/Akt stability and activation phosphorylation","volume":"28","author":"Liao","year":"2009","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.18632\/oncotarget.26691","article-title":"Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation","volume":"10","author":"Ueda","year":"2019","journal-title":"Oncotarget"},{"key":"ref_42","first-page":"1409","article-title":"Prolyl-isomerase Pin1 impairs trastuzumab sensitivity by up-regulating fatty acid synthase expression","volume":"34","author":"Yun","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"24255","DOI":"10.1074\/jbc.M115.658559","article-title":"Prolyl isomerase Pin1 negatively regulates AMP-activated protein kinase (AMPK) by associating with the CBS domain in the \u03b3 subunit","volume":"290","author":"Nakatsu","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"201S","DOI":"10.1038\/oby.2006.309","article-title":"Fatty acid metabolism, the central nervous system, and feeding","volume":"14","author":"Ronnett","year":"2006","journal-title":"Obesity"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1042\/bst0301064","article-title":"Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase","volume":"30","author":"Hardie","year":"2002","journal-title":"Biochem. Soc. Trans."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1111\/j.1432-1033.1997.00259.x","article-title":"The AMP-activated protein kinase\u2014fuel gauge of the mammalian cell?","volume":"246","author":"Hardie","year":"1997","journal-title":"Eur. J. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5166","DOI":"10.1210\/en.2003-0849","article-title":"Minireview: Malonyl CoA, AMP-activated protein kinase, and adiposity","volume":"144","author":"Ruderman","year":"2003","journal-title":"Endocrinology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13679-012-0037-4","article-title":"Fibrosis as a Cause or a Consequence of White Adipose Tissue Inflammation in Obesity","volume":"2","author":"Reggio","year":"2013","journal-title":"Curr. Obes. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"20812","DOI":"10.1074\/jbc.M110.206904","article-title":"Peptidyl-prolyl cis\/trans isomerase NIMA-interacting 1 associates with insulin receptor substrate-1 and enhances insulin actions and adipogenesis","volume":"286","author":"Nakatsu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11886","DOI":"10.1074\/jbc.M117.780726","article-title":"The prolyl isomerase Pin1 increases \u03b2-cell proliferation and enhances insulin secretion","volume":"292","author":"Nakatsu","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.mce.2016.07.030","article-title":"Pin1 enhances adipocyte differentiation by positively regulating the transcriptional activity of PPAR\u03b3","volume":"436","author":"Han","year":"2016","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1016\/j.freeradbiomed.2011.06.033","article-title":"Cross talk between mitochondria and NADPH oxidases","volume":"51","author":"Dikalov","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1177\/1479164113500680","article-title":"Cellular and molecular mechanisms of endothelial dysfunction in diabetes","volume":"10","author":"Roberts","year":"2013","journal-title":"Diabetes Vasc. Dis. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e12951","DOI":"10.1111\/eci.12951","article-title":"NADPH oxidase activation in neutrophils: Role of the phosphorylation of its subunits","volume":"48","author":"Belambri","year":"2018","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1042\/BJ20041835","article-title":"Activation and assembly of the NADPH oxidase: A structural perspective","volume":"386","author":"Groemping","year":"2005","journal-title":"Biochem. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4657","DOI":"10.4049\/jimmunol.1201007","article-title":"The TLR7\/8 agonist CL097 primes N-formyl-methionyl-leucyl-phenylalanine-stimulated NADPH oxidase activation in human neutrophils: Critical role of p47phox phosphorylation and the proline isomerase Pin1","volume":"189","author":"Boussetta","year":"2012","journal-title":"J. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5795","DOI":"10.1182\/blood-2010-03-273094","article-title":"The prolyl isomerase Pin1 acts as a novel molecular switch for TNF-alpha-induced priming of the NADPH oxidase in human neutrophils","volume":"116","author":"Boussetta","year":"2010","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jbior.2013.02.001","article-title":"PtdIns5P and Pin1 in oxidative stress signaling","volume":"53","author":"Keune","year":"2013","journal-title":"Adv. Biol. Regul."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nature10189","article-title":"Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis","volume":"475","author":"DeNicola","year":"2011","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.cell.2007.01.003","article-title":"FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress","volume":"128","author":"Tothova","year":"2007","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"21592","DOI":"10.1074\/jbc.M300931200","article-title":"Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression","volume":"278","author":"McMahon","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7130","DOI":"10.1128\/MCB.24.16.7130-7139.2004","article-title":"Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2","volume":"24","author":"Kobayashi","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1089\/ars.2010.3221","article-title":"Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway","volume":"13","author":"Hayes","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1016\/j.freeradbiomed.2010.03.013","article-title":"Role of Pin1 in neointima formation: Down-regulation of Nrf2-dependent heme oxygenase-1 expression by Pin1","volume":"48","author":"Kim","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"ra86","DOI":"10.1126\/scisignal.2003223","article-title":"Regulation of phosphatidylinositol-5-phosphate signaling by Pin1 determines sensitivity to oxidative stress","volume":"5","author":"Keune","year":"2012","journal-title":"Sci. Signal."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"a000034","DOI":"10.1101\/cshperspect.a000034","article-title":"The NF-kappaB family of transcription factors and its regulation","volume":"1","author":"Oeckinghaus","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.it.2013.01.004","article-title":"Regulation of nuclear factor-\u03baB in autoimmunity","volume":"34","author":"Sun","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/cr.2010.177","article-title":"Non-canonical NF-\u03baB signaling pathway","volume":"21","author":"Sun","year":"2011","journal-title":"Cell Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1006\/smim.2000.0210","article-title":"The I kappa B kinase (IKK) and NF-kappa B: Key elements of proinflammatory signalling","volume":"12","author":"Karin","year":"2000","journal-title":"Semin. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev.immunol.18.1.621","article-title":"Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity","volume":"18","author":"Karin","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nri910","article-title":"NF-kappaB regulation in the immune system","volume":"2","author":"Li","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"S81","DOI":"10.1016\/S0092-8674(02)00703-1","article-title":"Missing pieces in the NF-kappaB puzzle","volume":"109","author":"Ghosh","year":"2002","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S1097-2765(03)00490-8","article-title":"Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65\/RelA","volume":"12","author":"Ryo","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.4254\/wjh.v7.i23.2459","article-title":"Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma","volume":"7","author":"Takino","year":"2015","journal-title":"World J. Hepatol."},{"key":"ref_76","first-page":"751","article-title":"Hepatic stellate cells secretes type I collagen to trigger epithelial mesenchymal transition of hepatoma cells","volume":"4","author":"Yang","year":"2014","journal-title":"Am. J. Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0092-8674(00)00116-1","article-title":"Signal transduction by the JNK group of MAP kinases","volume":"103","author":"Davis","year":"2000","journal-title":"Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/cdd.2011.82","article-title":"A critical step for JNK activation: Isomerization by the prolyl isomerase Pin1","volume":"19","author":"Park","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1152\/physrev.2001.81.2.807","article-title":"Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation","volume":"81","author":"Kyriakis","year":"2001","journal-title":"Physiol. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4589","DOI":"10.1158\/0008-5472.CAN-08-4117","article-title":"Peptidyl-prolyl isomerase Pin1 markedly enhances the oncogenic activity of the rel proteins in the nuclear factor-kappaB family","volume":"69","author":"Fan","year":"2009","journal-title":"Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1159\/000365415","article-title":"Can serum pin1 level be regarded as an indicative marker of nonalcoholic steatohepatitis and fibrotic stages?","volume":"90","author":"Cengiz","year":"2014","journal-title":"Digestion"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.pharmthera.2012.05.001","article-title":"Transforming growth factor (TGF)-\u03b2 expression and activation mechanisms as potential targets for anti-tumor therapy and tumor imaging","volume":"135","author":"Arjaans","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s11912-006-0043-3","article-title":"Integrins: Molecular targets in cancer therapy","volume":"8","author":"Tucker","year":"2006","journal-title":"Curr. Oncol. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.biocel.2007.09.006","article-title":"How the Smads regulate transcription","volume":"40","author":"Ross","year":"2008","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S0092-8674(00)81249-0","article-title":"Xenopus Mad proteins transduce distinct subsets of signals for the TGF beta superfamily","volume":"85","author":"Graff","year":"1996","journal-title":"Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/383168a0","article-title":"Receptor-associated Mad homologues synergize as effectors of the TGF-beta response","volume":"383","author":"Zhang","year":"1996","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/383832a0","article-title":"Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways","volume":"383","author":"Lagna","year":"1996","journal-title":"Nature"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1074\/jbc.M109.063826","article-title":"Pin1 promotes transforming growth factor-beta-induced migration and invasion","volume":"285","author":"Matsuura","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1101\/gad.2060811","article-title":"A Smad action turnover switch operated by WW domain readers of a phosphoserine code","volume":"25","author":"Goerner","year":"2011","journal-title":"Genes Dev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1038\/onc.2009.232","article-title":"The prolyl isomerase Pin1 regulates the NF-kappaB signaling pathway and interleukin-8 expression in glioblastoma","volume":"28","author":"Atkinson","year":"2009","journal-title":"Oncogene"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1038\/ni1266","article-title":"The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils","volume":"6","author":"Shen","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"6263","DOI":"10.1002\/jcp.27357","article-title":"TGF-\u03b21-PML SUMOylation-peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) form a positive feedback loop to regulate cardiac fibrosis","volume":"234","author":"Wu","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"23294","DOI":"10.1074\/jbc.M111.313684","article-title":"Pin1 protein regulates Smad protein signaling and pulmonary fibrosis","volume":"287","author":"Shen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.bbadis.2014.07.025","article-title":"Stat3 signaling activation crosslinking of TGF-\u03b21 in hepatic stellate cell exacerbates liver injury and fibrosis","volume":"1842","author":"Xu","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1053\/jhep.2002.32029","article-title":"Leptin in hepatic fibrosis: Evidence for increased collagen production in stellate cells and lean littermates of ob\/ob mice","volume":"35","author":"Saxena","year":"2002","journal-title":"Hepatology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1091\/mbc.E17-06-0342","article-title":"STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis posttranscriptionally, and is essential for lung myofibroblast differentiation","volume":"29","author":"Papaioannou","year":"2018","journal-title":"Mol. Biol. Cell"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Kasembeli, M.M., Bharadwaj, U., Robinson, P., and Tweardy, D.J. (2018). Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082299"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"9952","DOI":"10.1074\/jbc.M113.545822","article-title":"Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-\u03b2 (TGF-\u03b2) signaling promoting SMAD3 activation and fibrosis via Gremlin protein","volume":"289","author":"Ciechomska","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"7656","DOI":"10.1038\/sj.onc.1210567","article-title":"Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity","volume":"26","author":"Lufei","year":"2007","journal-title":"Oncogene"},{"key":"ref_100","unstructured":"Nakatsu, Y., Matsunaga, Y., Ueda, K., Yamamotoya, T., Inoue, Y., Inoue, M.K., Mizuno, Y., Kushiyama, A., Ono, H., and Fujishiro, M. (2018). Development of Pin1 inhibitors and their potential as therapeutic agents. Curr. Med. Chem., 5."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1545\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:38:49Z","timestamp":1760189929000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1545"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,29]]},"references-count":100,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["cells8121545"],"URL":"https:\/\/doi.org\/10.3390\/cells8121545","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,29]]}}}