Zhu Sitong, Liao Lei, Zhong Yi, Liu Zhenming, Lu Junfeng, Yang Zhiwei, Xiao Yibei, Xu Xiaojun
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China; Department of Pharmacy, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China Center for Innovative Traditional Chinese Medicine Target and New Drug Research, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, China.
J Hepatol. 2025 Jan 22. doi: 10.1016/j.jhep.2025.01.008.
BACKGROUND & AIMS: There are limited pharmacological treatment options for metabolic dysfunction-associated steatohepatitis (MASH), the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, we aimed to identify novel therapeutic targets. METHODS: The Gene Expression Omnibus database and human liver tissues obtained from patients with MASH were used to identify differentially expressed genes in MASH. The functional role of cytidine/uridine monophosphate kinase 2 (CMPK2) was assessed in mice with hepatocyte-specific overexpression, conditional knockout mice, and several murine MASH models. CMPK2 inhibitors were discovered through surface plasmon resonance imaging coupled with indirect enzyme activity detection. RESULTS: CMPK2, a critical enzyme involved in mitochondrial DNA synthesis, exhibited significant upregulation in the livers of obese individuals with MASH and mice with diet-induced MASH. Hepatocyte-specific Cmpk2 deletion substantially mitigated liver injury, inflammation, and fibrosis in mice. Inhibition of CMPK2, either through genetic manipulation or pharmacological intervention with nordihydroguaiaretic acid, suppressed Nlrp3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation and subsequent hepatic pyroptosis. Furthermore, nordihydroguaiaretic acid alleviated diet-induced metabolic disorders, inflammation, and fibrosis in vivo. CONCLUSIONS: These findings establish CMPK2 as a critical mediator in the progression from metabolic dysfunction-associated steatotic liver to MASH and highlight its potential as a therapeutic target for metabolic diseases. IMPACT AND IMPLICATIONS: Cytidine/uridine monophosphate kinase 2 (CMPK2) is upregulated in the metabolic dysfunction-associated steatohepatitis (MASH) stage but not in the early stages of metabolic dysfunction-associated steatotic liver disease. Our study demonstrated that diet-induced MASH phenotypes, including liver injury, inflammation, and fibrosis were alleviated in hepatocyte-specific Cmpk2-knockout mice. These findings suggest that CMPK2 serves as a critical link in the progression of steatotic liver to steatohepatitis, offering novel mechanistic insights into MASH development. Furthermore, this discovery identified CMPK2 as a promising target for the development of therapeutic drugs for MASH.
背景与目的：代谢功能障碍相关脂肪性肝炎（MASH）是代谢功能障碍相关脂肪性肝病（MASLD）的进展形式，其药物治疗选择有限。因此，我们旨在确定新的治疗靶点。 方法：利用基因表达综合数据库和从MASH患者获取的人肝组织，确定MASH中差异表达的基因。在肝细胞特异性过表达小鼠、条件性敲除小鼠和几种小鼠MASH模型中评估胞苷/尿苷单磷酸激酶2（CMPK2）的功能作用。通过表面等离子体共振成像结合间接酶活性检测发现CMPK2抑制剂。 结果：CMPK2是参与线粒体DNA合成的关键酶，在患有MASH的肥胖个体肝脏和饮食诱导的MASH小鼠肝脏中显著上调。肝细胞特异性Cmpk2缺失可显著减轻小鼠的肝损伤、炎症和纤维化。通过基因操作或用去甲二氢愈创木酸进行药物干预抑制CMPK2，可抑制Nlrp3（含吡啉结构域的NOD样受体家族3）炎性小体激活及随后的肝脏细胞焦亡。此外，去甲二氢愈创木酸可减轻饮食诱导的体内代谢紊乱、炎症和纤维化。 结论：这些发现确立了CMPK2是代谢功能障碍相关脂肪性肝病进展为MASH的关键介质，并突出了其作为代谢性疾病治疗靶点的潜力。 影响与意义：胞苷/尿苷单磷酸激酶2（CMPK2）在代谢功能障碍相关脂肪性肝炎（MASH）阶段上调，但在代谢功能障碍相关脂肪性肝病早期阶段未上调。我们的研究表明，在肝细胞特异性Cmpk2敲除小鼠中，饮食诱导的MASH表型，包括肝损伤、炎症和纤维化得到缓解。这些发现表明CMPK2是脂肪性肝病进展为脂肪性肝炎的关键环节，为MASH的发展提供了新的机制见解。此外，这一发现确定CMPK2是开发MASH治疗药物的有前景的靶点。
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