{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:45:02Z","timestamp":1790959502380,"version":"4.1.0"},"reference-count":58,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,2]],"date-time":"2022-10-02T00:00:00Z","timestamp":1664668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972689"],"award-info":[{"award-number":["81972689"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["CIT&TCD20190311"],"award-info":[{"award-number":["CIT&TCD20190311"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Great Wall Scholar Project","award":["81972689"],"award-info":[{"award-number":["81972689"]}]},{"name":"Great Wall Scholar Project","award":["CIT&TCD20190311"],"award-info":[{"award-number":["CIT&TCD20190311"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver fibrosis is a wound-healing response caused by the abnormal accumulation of extracellular matrix, which is produced by activated hepatic stellate cells (HSCs). Most studies have focused on the activated HSCs themselves in liver fibrosis, and whether hepatocytes can modulate the process of fibrosis is still unclear. Sma mothers against decapentaplegic homologue 4 (Smad4) is a key intracellular transcription mediator of transforming growth factor-\u03b2 (TGF-\u03b2) during the development and progression of liver fibrosis. However, the role of hepatocyte Smad4 in the development of fibrosis is poorly elucidated. Here, to explore the functional role of hepatocyte Smad4 and the molecular mechanism in liver fibrosis, a CCl4-induced liver fibrosis model was established in mice with hepatocyte-specific Smad4 deletion (Smad4\u0394hep). We found that hepatocyte-specific Smad4 deficiency reduced liver inflammation and fibrosis, alleviated epithelial-mesenchymal transition, and inhibited hepatocyte proliferation and migration. Molecularly, Smad4 deletion in hepatocytes suppressed the expression of inhibitor of differentiation 1 (ID1) and the secretion of connective tissue growth factor (CTGF) of hepatocytes, which subsequently activated the p38 and p65 signaling pathways of HSCs in an epidermal growth factor receptor-dependent manner. Taken together, our results clearly demonstrate that the Smad4 expression in hepatocytes plays an important role in promoting liver fibrosis and could therefore be a promising target for future anti-fibrotic therapy.<\/jats:p>","DOI":"10.3390\/ijms231911696","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T22:19:27Z","timestamp":1665267567000},"page":"11696","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Hepatocyte-Specific Smad4 Deficiency Alleviates Liver Fibrosis via the p38\/p65 Pathway"],"prefix":"10.3390","volume":"23","author":[{"given":"Miaomiao","family":"Wei","sequence":"first","affiliation":[{"name":"The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlong","family":"Yan","sequence":"additional","affiliation":[{"name":"Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing 100124, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xin","sequence":"additional","affiliation":[{"name":"The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiqiang","family":"Chen","sequence":"additional","affiliation":[{"name":"The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Hou","sequence":"additional","affiliation":[{"name":"The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8957-8893","authenticated-orcid":false,"given":"Jinhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41575-020-00372-7","article-title":"Molecular and cellular mechanisms of liver fibrosis and its regression","volume":"18","author":"Kisseleva","year":"2021","journal-title":"Nat. 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