{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:04:35Z","timestamp":1789664675515,"version":"4.0.1"},"reference-count":50,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,7,4]],"date-time":"2021-07-04T00:00:00Z","timestamp":1625356800000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2017ZX09101002\u2010002\u2010005"],"award-info":[{"award-number":["2017ZX09101002\u2010002\u2010005"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009018","name":"Shanghai Municipal Human Resources and Social Security Bureau","doi-asserted-by":"publisher","award":["2018060"],"award-info":[{"award-number":["2018060"]}],"id":[{"id":"10.13039\/501100009018","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Liver fibrosis and fibrosis\u2010related hepatocarcinogenesis are a rising cause for morbidity and death worldwide. Although transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2) is a critical mediator of chronic liver fibrosis, targeting TGF\u2010\u03b2 isoforms and receptors lead to unacceptable side effect. This study was designed to explore the antifibrotic effect of Compound kushen injection (CKI), an approved traditional Chinese medicine formula, via a therapeutic strategy of rebalancing TGF\u2010\u03b2\/Smad7 signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A meta\u2010analysis was performed to evaluate CKI intervention on viral hepatitis\u2010induced fibrosis or cirrhosis in clinical randomized controlled trials (RCTs). Mice were given carbon tetrachloride (CCl\n                      <jats:sub>4<\/jats:sub>\n                      ) injection or methionine\u2010choline deficient (MCD) diet to induce liver fibrosis, followed by CKI treatment. We examined the expression of TGF\u2010\u03b2\/Smad signaling and typical fibrosis\u2010related genes in hepatic stellate cells (HSCs) and fibrotic liver tissues by qRT\u2010PCR, Western blotting, RNA\u2010seq, immunofluorescence, and immunohistochemistry.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Based on meta\u2010analysis results, CKI improved the liver function and relieved liver fibrosis among patients. In our preclinical studies by using two mouse models, CKI treatment demonstrated promising antifibrotic effects and postponed hepatocarcinogenesis with improved liver function and histopathologic features. Mechanistically, we found that CKI inhibited HSCs activation by stabilizing the interaction of Smad7\/TGF\u2010\u03b2R1 to rebalance Smad2\/Smad3 signaling, and subsequently decreased the extracellular matrix formation. Importantly, Smad7 depletion abolished the antifibrotic effect of CKI in vivo and in vitro. Moreover, matrine, oxymatrine, sophocarpine, and oxysophocarpine were identified as material basis responsible for the antifibrosis effect of CKI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results unveil the approach of CKI in rebalancing TGF\u2010\u03b2\/Smad7 signaling in HSCs to protect against hepatic fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. Our study suggests that CKI can be a candidate for treatment of hepatic fibrosis and related oncogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.410","type":"journal-article","created":{"date-parts":[[2021,7,4]],"date-time":"2021-07-04T10:38:41Z","timestamp":1625395121000},"source":"Crossref","is-referenced-by-count":96,"title":["Rebalancing TGF\u2010\u03b2\/Smad7 signaling via Compound kushen injection in hepatic stellate cells protects against liver fibrosis and hepatocarcinogenesis"],"prefix":"10.1002","volume":"11","author":[{"given":"Yang","family":"Yang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weida","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaobao","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheshun","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Gu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingquan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Zhendong Pharmaceutical Research Institute Co., Ltd.  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