Hepatocellular CMPK2 promotes the development of metabolic dysfunction-associated steatohepatitis

Abstract

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.

Keywords: CMPK2; MASH; NLRP3 inflammasome; pyroptosis.