Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Clin Transl Med. 2023 Jul;13(7):e1316. doi: 10.1002/ctm2.1316.
As a central event during liver fibrosis, hepatic stellate cells (HSC) have been thought to be a potential therapeutic target for liver fibrosis. Previous studies have shown that runt-related transcription factor 2 (Runx2) is associated with the development of non-alcoholic fatty liver disease, while its specific role in HSC activation and hepatic fibrosis remains elusive.
In this study, we found that Runx2 expression was significantly upregulated in human liver fibrosis with different aetiologies. Runx2 expression was also gradually elevated in mouse liver during fibrosis, and Runx2 was mainly expressed in the activated HSC. Knockdown of Runx2 in HSC markedly alleviated CCl -induced, 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced or methionine-choline deficient (MCD)-induced liver fibrosis, while hepatic overexpression of Runx2 via HBAAV-Runx2 or VA-Lip-Runx2 injection exacerbated CCl -induced liver fibrosis. In vitro analysis demonstrated that Runx2 promoted HSC activation and proliferation, whereas Runx2 knockdown in HSC suppressed these effects. RNA-seq and Runx2 ChIP-seq analysis demonstrated that Runx2 could promote integrin alpha-V (Itgav) expression by binding to its promoter. Blockade of Itgav attenuated Runx2-induced HSC activation and liver fibrosis. Additionally, we found that cytokines (TGF-β1, PDGF, EGF) promote the expression and nuclear translocation of Runx2 through protein kinase A (PKA) in HSC.
Runx2 is critical for HSC activation via transcriptionally regulating Itgav expression during liver fibrosis, and may be a promising therapeutic target for liver fibrosis.
肝星状细胞（HSC）作为肝纤维化过程中的一个核心事件，被认为是肝纤维化的一个潜在治疗靶点。先前的研究表明， runt 相关转录因子 2（Runx2）与非酒精性脂肪性肝病的发展有关，但其在 HSC 激活和肝纤维化中的具体作用仍不清楚。
在这项研究中，我们发现 Runx2 在不同病因的人类肝纤维化中表达明显上调。Runx2 在小鼠肝纤维化过程中也逐渐升高，主要表达于激活的 HSC 中。在 HSC 中敲低 Runx2 可显著减轻 CCl4 诱导、3,5-二乙氧基羰基-1,4-二氢吡啶诱导或蛋氨酸-胆碱缺乏（MCD）诱导的肝纤维化，而通过 HBAAV-Runx2 或 VA-Lip-Runx2 注射过表达 Runx2 则加剧 CCl4 诱导的肝纤维化。体外分析表明 Runx2 促进 HSC 激活和增殖，而 HSC 中 Runx2 的敲低抑制了这些作用。RNA-seq 和 Runx2 ChIP-seq 分析表明，Runx2 可以通过结合其启动子促进整合素 alpha-V（Itgav）的表达。Itgav 阻断减弱了 Runx2 诱导的 HSC 激活和肝纤维化。此外，我们发现细胞因子（TGF-β1、PDGF、EGF）通过蛋白激酶 A（PKA）在 HSC 中促进 Runx2 的表达和核转位。
Runx2 通过转录调控肝纤维化过程中 Itgav 的表达，对 HSC 的激活至关重要，可能是肝纤维化的一个有前途的治疗靶点。
