{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T12:35:51Z","timestamp":1791722151295,"version":"4.3.4"},"reference-count":49,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"740","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,3,27]]},"abstract":"<jats:p>\n            Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis\u2013associated (\n            <jats:italic>ENHO<\/jats:italic>\n            ) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin\/\n            <jats:italic>ENHO<\/jats:italic>\n            in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGF\u03b2 reduced adropin\/\n            <jats:italic>ENHO<\/jats:italic>\n            expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin\n            <jats:sup>34\u201376<\/jats:sup>\n            peptides in turn inhibited TGF\u03b2-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of\n            <jats:italic>GPR19<\/jats:italic>\n            , an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin\n            <jats:sup>34\u201376<\/jats:sup>\n            were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin\n            <jats:sup>34\u201376<\/jats:sup>\n            -induced changes in TGF\u03b2\/GLI1 signaling. Our study characterizes the TGF\u03b2-induced down-regulation of adropin\/\n            <jats:italic>ENHO<\/jats:italic>\n            expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.add6570","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T18:00:54Z","timestamp":1711562454000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":31,"title":["Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7650-1237","authenticated-orcid":true,"given":"Minrui","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Division of Rheumatology, Huashan Rare Disease Center, Huashan Hospital, Fudan University, 200032 Shanghai, P. R. China."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-7662","authenticated-orcid":true,"given":"Nicholas","family":"Dickel","sequence":"additional","affiliation":[{"name":"Chair of Medical Informatics, Friedrich-Alexander University (FAU), Erlangen-N\u00fcrnberg, 91058 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea-Hermina","family":"Gy\u00f6rfi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilgesu","family":"SafakT\u00fcmerdem","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-9361","authenticated-orcid":true,"given":"Yi-Nan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleix Rius","family":"Rigau","sequence":"additional","affiliation":[{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0305-2522","authenticated-orcid":true,"given":"Chunguang","family":"Liang","sequence":"additional","affiliation":[{"name":"Chair of Medical Informatics, Friedrich-Alexander University (FAU), Erlangen-N\u00fcrnberg, 91058 Erlangen, Germany."},{"name":"Institute of Immunology, Jena University Hospital, 07743 Jena, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuezhi","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lichong","family":"Shen","sequence":"additional","affiliation":[{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."},{"name":"Division of Rheumatology, Renji Hospital, Shanghai Jiao Tong University, 200001 Shanghai, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1248-3145","authenticated-orcid":true,"given":"Alexandru-Emil","family":"Matei","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuong","family":"Trinh-Minh","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuong","family":"Tran-Manh","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-6044","authenticated-orcid":true,"given":"Ariella","family":"Zehender","sequence":"additional","affiliation":[{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2275-499X","authenticated-orcid":true,"given":"Alexander","family":"Kreuter","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, HELIOS Sankt Elisabeth Klinik Oberhausen, 46045 Oberhausen, Nordrhein-Westfalen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9762-2663","authenticated-orcid":true,"given":"Hejian","family":"Zou","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Huashan Rare Disease Center, Huashan Hospital, Fudan University, 200032 Shanghai, P. 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W.","family":"Distler","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Hiller Research Unit, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University; 40225 D\u00fcsseldorf, Germany."},{"name":"Rheumatology and Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander-University (FAU) Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany."},{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-N\u00fcrnberg and University Hospital Erlangen, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-019-0322-7"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)30933-9"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI74368"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.90"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.2277"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2017.12.016"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.10.011"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.008967"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.007528"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03610-1"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2021.10.032"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.931782"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2017.05.001"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-215894"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.39289"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24607-6"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209698"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00511.2015"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2017.12.002"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204401"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3777"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204378"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2015.01.005"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12987-022-00363-7"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfw102"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI74929"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.34444"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200883"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-215066"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-01-403428"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.12.022"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2014.11.004"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2016.54"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.03.075"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19051293"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204424"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI122462"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201916"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020008720"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.41058"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0896-x"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2014.145"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24601-y"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz5506"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.2144\/000112729"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejrad.2012.02.021"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1734"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-18-0782"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.38101"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.add6570","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T18:00:57Z","timestamp":1711562457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.add6570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,27]]},"references-count":49,"journal-issue":{"issue":"740","published-print":{"date-parts":[[2024,3,27]]}},"alternative-id":["10.1126\/scitranslmed.add6570"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.add6570","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,27]]},"assertion":[{"value":"2022-09-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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