Hepatocellular CMPK2 promotes the development of metabolic dysfunction-associated steatohepatitis.

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.