Shi Fengchun, Tan Wei, Huang Wei, Ye Fei, Wang Mingjie, Wang Yongxiang, Zhang Xinxin, Yu Demin
Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226000, China.
Virol J. 2025 Apr 26;22(1):120. doi: 10.1186/s12985-025-02749-z.
Chronic hepatitis B (CHB) remains a global health challenge, with liver fibrosis serving as a critical determinant of disease progression. Despite antiviral treatments, liver fibrosis often persists in CHB patients, highlighting the need for additional biomarkers and therapeutic targets. This study investigates the molecular mechanism underlying HBV-induced liver fibrosis, focusing on the role of RUNX2 in regulating integrin beta-like 1 (ITGBL1), a key factor in fibrogenesis.
We examined the relationship between RUNX2 and ITGBL1 in both in vitro hepatocyte models and an in vivo HBV mouse model. Using chromatin immunoprecipitation (ChIP), luciferase reporter assays, and Western blotting, we assessed RUNX2 binding to the ITGBL1 promoter and its impact on gene expression. We also evaluated the effects of RUNX2 inhibition using Vitamin D3 and CADD522 on ITGBL1 expression and hepatic stellate cell activation.
Our findings reveal that RUNX2 directly binds to the ITGBL1 promoter, enhancing its expression and promoting hepatic stellate cell activation. We show that HBV infection significantly upregulates both RUNX2 and ITGBL1 in liver cells. Inhibition of RUNX2 with Vitamin D3 or CADD522 significantly reduced ITGBL1 levels and blocked hepatic stellate cell activation. These results suggest that the RUNX2/ITGBL1 pathway is critical in the progression of liver fibrosis in HBV-infected patients.
RUNX2 promotes liver fibrosis in HBV-infected patients by upregulating ITGBL1 expression. Our findings suggest that targeting RUNX2 could be a potential therapeutic approach to mitigate liver fibrosis in chronic hepatitis B.
慢性乙型肝炎（CHB）仍然是一项全球性的健康挑战，肝纤维化是疾病进展的关键决定因素。尽管有抗病毒治疗，但CHB患者的肝纤维化往往持续存在，这凸显了对额外生物标志物和治疗靶点的需求。本研究调查了HBV诱导肝纤维化的分子机制，重点关注RUNX2在调节整合素β样1（ITGBL1）中的作用，ITGBL1是纤维化形成的关键因素。
我们在体外肝细胞模型和体内HBV小鼠模型中研究了RUNX2与ITGBL1之间的关系。使用染色质免疫沉淀（ChIP）、荧光素酶报告基因检测和蛋白质免疫印迹，我们评估了RUNX2与ITGBL1启动子的结合及其对基因表达的影响。我们还评估了使用维生素D3和CADD522抑制RUNX2对ITGBL1表达和肝星状细胞激活的影响。
我们的研究结果表明，RUNX2直接与ITGBL1启动子结合，增强其表达并促进肝星状细胞激活。我们发现HBV感染显著上调肝细胞中RUNX2和ITGBL1的表达。用维生素D3或CADD522抑制RUNX2可显著降低ITGBL1水平并阻断肝星状细胞激活。这些结果表明，RUNX2/ITGBL1通路在HBV感染患者肝纤维化进展中至关重要。
RUNX2通过上调ITGBL1表达促进HBV感染患者的肝纤维化。我们的研究结果表明，靶向RUNX2可能是减轻慢性乙型肝炎肝纤维化的一种潜在治疗方法。
