Rebalancing TGF‐β/Smad7 signaling via Compound kushen injection in hepatic stellate cells protects against liver fibrosis and hepatocarcinogenesis

作者：Yang Yang, Mayu Sun, Weida Li, Chaobao Liu, Zheshun Jiang, Pengfei Gu, Jingquan Li, Wei Wang, Rongli You, Qian Ba, Xiaoguang Li, Hui Wang · 发表于：Clinical and Translational Medicine · 年份：2021 · DOI：10.1002/ctm2.410 · 被引用次数：98 · 研究领域：Liver physiology and pathology、Liver Disease Diagnosis and Treatment、Bioactive Compounds in Plants

BACKGROUND: Liver fibrosis and fibrosis-related hepatocarcinogenesis are a rising cause for morbidity and death worldwide. Although transforming growth factor-β (TGF-β) is a critical mediator of chronic liver fibrosis, targeting TGF-β 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-β/Smad7 signaling. METHODS: ) injection or methionine-choline deficient (MCD) diet to induce liver fibrosis, followed by CKI treatment. We examined the expression of TGF-β/Smad signaling and typical fibrosis-related genes in hepatic stellate cells (HSCs) and fibrotic liver tissues by qRT-PCR, Western blotting, RNA-seq, immunofluorescence, and immunohistochemistry. RESULTS: Based on meta-analysis 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-βR1 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, oxymatri...