Lyu Shi-Yi, Xiao Wang, Chen Yan-Jing, Liao Qiu-Ling, Cai Ye-Yu, Yu Cheng, Liu Jia-Yi, Liu Huan, Zhang Min-Ping, Ren Yu-Lu, Yu Qi-Ling, Qi Yi-Ming, Xiao En-Hua, Luo Yong-Heng
Department of Radiology, Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China.
Department of Gastrointestinal Surgery, Yiyang Central Hospital, Yiyang 413099, Hunan Province, China.
World J Gastroenterol. 2025 May 28;31(20):105554. doi: 10.3748/wjg.v31.i20.105554.
Hepatic stellate cell (HSC) activation is key to liver fibrosis. Targeting DNA methylation shows promise. Zebularine, a methylation inhibitor, may suppress HSC activation the calcineurin (CaN)/ pathway. Magnetic resonance imaging (MRI) is a noninvasive tool for evaluating liver fibrosis evaluation tool, but multiparametric MRI for zebularine's effects in liver fibrosis mouse models has not been studied.
To clarify the anti-fibrosis mechanism and MRI-evaluated efficacy of zebularine.
, transforming growth factor (TGF)-β1-stimulated human HSCs (LX-2) were treated with zebularine. α-smooth muscle actin, fibrotic and anti-fibrotic gene levels, and regulator of calcineurin1 (RCAN1) regulation were measured. , carbon tetrachloride (CCl)-induced liver fibrosis in mice was treated with zebularine, and fibrosis was evaluated using various biochemical, histopathological, and MRI methods.
Zebularine upregulated RCAN1.4 protein ( < 0.01) and inhibited the CaN/ pathway ( < 0.05). In HSCs, TGF-β1 reduced anti-fibrotic gene massage RNA (mRNA) and increased fibrotic mRNA ( < 0.05), whereas zebularine had the opposite effects ( < 0.01, < 0.05). CCl-treated mice exhibited increases in various fibrosis-related indices, all of which were reversed by zebularine treatment ( < 0.05).
Zebularine may reduce LX-2 activation and extracellular matrix deposition RCAN1.4 and CaN/ pathways. Multiparametric MRI can assess its efficacy, suggesting zebularine's potential as a liver fibrosis treatment.
肝星状细胞（HSC）激活是肝纤维化的关键。靶向DNA甲基化显示出前景。zebularine是一种甲基化抑制剂，可能通过钙调神经磷酸酶（CaN）/ 途径抑制HSC激活。磁共振成像（MRI）是评估肝纤维化的一种非侵入性工具，但尚未研究多参数MRI对zebularine在肝纤维化小鼠模型中作用的评估。
阐明zebularine的抗纤维化机制及MRI评估的疗效。
用zebularine处理转化生长因子（TGF）-β1刺激的人HSCs（LX-2）。检测α-平滑肌肌动蛋白、纤维化和抗纤维化基因水平以及钙调神经磷酸酶调节因子1（RCAN1）的调节情况。用zebularine处理四氯化碳（CCl）诱导的小鼠肝纤维化，并使用各种生化、组织病理学和MRI方法评估纤维化情况。
zebularine上调了RCAN1.4蛋白（<0.01）并抑制了CaN/ 途径（<0.05）。在HSCs中，TGF-β1降低了抗纤维化基因信使核糖核酸（mRNA）并增加了纤维化mRNA（<0.05），而zebularine则有相反的作用（<0.01，<0.05）。CCl处理的小鼠各种纤维化相关指标均升高，而zebularine处理可使其逆转（<0.05）。
zebularine可能通过RCAN1.4和CaN/ 途径减少LX-2激活和细胞外基质沉积。多参数MRI可评估其疗效，提示zebularine作为肝纤维化治疗药物的潜力。
