{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:14:49Z","timestamp":1791292489494,"version":"4.1.0"},"reference-count":42,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2019YFA0802003"],"award-info":[{"award-number":["2019YFA0802003"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82000555"],"award-info":[{"award-number":["82000555"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81822006"],"award-info":[{"award-number":["81822006"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81500439"],"award-info":[{"award-number":["81500439"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82170635"],"award-info":[{"award-number":["82170635"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82170591"],"award-info":[{"award-number":["82170591"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin","doi-asserted-by":"crossref","award":["20JCYBJC01120"],"award-info":[{"award-number":["20JCYBJC01120"]}],"id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,8]]},"abstract":"<jats:p>Nonalcoholic steatohepatitis (NASH) is closely related to liver fibrosis. The role of coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) in NASH remains unknown. CHCHD2\u2019s functions as a transcription factor have received much less attention than those in mitochondria. Herein, we systematically characterized the role of CHCHD2 as a transcription factor by chromatin immunoprecipitation sequencing and found its target genes were enriched in nonalcoholic fatty liver disease (NAFLD). Overall, CHCHD2 expression was found to be increased in the livers of patients with NAFLD and those of NASH mice. In line with these findings, CHCHD2 deficiency ameliorated NASH- and thioacetamide-induced liver fibrosis, whereas hepatocyte-specific CHCHD2 overexpression promoted liver fibrosis in NASH mice via Notch signaling. Specifically, CHCHD2-overexpressing hepatocytes activated hepatic stellate cells by upregulating osteopontin levels, a downstream mediator of Notch signals. Moreover, Notch inhibition attenuated CHCHD2 overexpression\u2013induced liver fibrosis in vivo and in vitro. Then we found lipopolysaccharide-induced CHCHD2 expression in hepatocytes was reverted by verteporfin, an inhibitor that disrupts the interaction between Yes-associated protein (YAP) and transcriptional enhanced associate domains (TEADs). In addition, CHCHD2 levels were positively correlated with those of TEAD1 in human samples. In conclusion, CHCHD2 is upregulated via YAP\/TAZ-TEAD in NASH livers and consequently promotes liver fibrosis by activating the Notch pathway and enhancing osteopontin production.<\/jats:p>","DOI":"10.1172\/jci.insight.162402","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T14:01:03Z","timestamp":1670421663000},"source":"Crossref","is-referenced-by-count":20,"title":["Increased CHCHD2 expression promotes liver fibrosis in nonalcoholic steatohepatitis via Notch\/osteopontin signaling"],"prefix":"10.1172","volume":"7","author":[{"given":"Yue","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Xiu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangmei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjie","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Xie","sequence":"additional","affiliation":[{"name":"Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyin","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7464-267X","authenticated-orcid":true,"given":"Chunjiong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2022,12,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1503519"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.06.003"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2014.10.003"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.194"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1454"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.3256"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9020184"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.11.311"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.06.005"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aat0344"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13806"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/cells8060600"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30928"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.04.033"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.09.016"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2018.09.011"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.07.030"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-020-00365-6"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30990"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2021.06.003"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-020-1779-2"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.12290"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nature10809"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2021.01.021"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.660843"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70266-2"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2018.9686"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-019-5575-7"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-020-1079-0"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.7150\/jca.31158"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2378"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.02.026"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2018.03.001"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20303-z"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25534"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.01.040"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32332"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13844"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.21142.1"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv145"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/162402\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T22:00:53Z","timestamp":1779141653000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/162402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,8]]},"references-count":42,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12,8]]},"published-print":{"date-parts":[[2022,12,8]]}},"alternative-id":["10.1172\/jci.insight.162402"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.162402","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,8]]},"article-number":"e162402"}}