Hepatocellular CMPK2 promotes the development of metabolic dysfunction-associated steatohepatitis

Sitong Zhu; Lei Liao; Yi Zhong; Zhenming Liu; Junfeng Lu; Zhiwei Yang; Yibei Xiao; Xiaojun Xu

doi:10.1016/j.jhep.2025.01.008

Hepatocellular CMPK2 promotes the development of metabolic dysfunction-associated steatohepatitis

J Hepatol. 2025 Jan 22:S0168-8278(25)00014-5. doi: 10.1016/j.jhep.2025.01.008. Online ahead of print.

Authors

Sitong Zhu¹, Lei Liao², Yi Zhong³, Zhenming Liu³, Junfeng Lu⁴, Zhiwei Yang⁵, Yibei Xiao⁶, Xiaojun Xu⁷

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China.
² 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, Center for Innovative Traditional Chinese Medicine Target and New Drug Research, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, China.
³ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
⁴ First Department of Liver Disease, Beijing You'An Hospital, Capital Medical University, Beijing 100069, China.
⁵ Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical Collage (PUMC), Beijing, 100021, PR China.
⁶ State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China. Electronic address: yibei.xiao@cpu.edu.cn.
⁷ 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, Center for Innovative Traditional Chinese Medicine Target and New Drug Research, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, China. Electronic address: xiaojunxu@zju.edu.cn.

PMID: 39855350
DOI: 10.1016/j.jhep.2025.01.008

Abstract

Background & aims: Metabolic dysfunction-associated steatohepatitis (MASH), a progressive subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), has limited pharmacological treatment options. Therefore, we aimed to identify novel therapeutic targets.

Methods: The Gene Expression Omnibus (GEO) 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 (NDGA), suppressed NOD-like receptor family pyrin domain containing 3 (Nlrp3) inflammasome activation and subsequent hepatic pyroptosis. Furthermore, NDGA 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 (MASL) to MASH and highlight its potential as a therapeutic target for metabolic diseases.

Impact and implications: CMPK2 exhibits upregulated in the MASH stage but not in the early stages of MASLD. 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 serve as a critical link in the progression of steatotic liver to steatohepatitis, offering novel mechanistic insights MASH development. Furthermore, this discovery identified CMPK2 as a promising target for the development of therapeutic drugs for MASH.

Keywords: CMPK2; MASH; NLRP3 inflammasome; pyroptosis.