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Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA. N-acetyltransferase 10 (NAT10) has not been fully explored in MASLD and MASH. Methods: The clinical relevance of NAT10 was evaluated based on its expression in various mouse and human models of MASLD and MASH. Acetylated RNA immunoprecipitation sequencing and mRNA stability assays were used to explore the role of NAT10 in regulating ac4C modification and expression of target genes. Genetically engineered mice were employed to investigate the role of NAT10 in MASLD and MASH progression. Results: Hepatic NAT10 expression was significantly increased in multiple mice and humans of MASLD and MASH. Genetic knockout of NAT10 protected mice from diet-induced hepatic steatosis and steatohepatitis, whereas overexpression of NAT10 exacerbated high-fat-diet-induced liver steatosis. Mechanistically, NAT10 binds to Srebp-1c mRNA, promoting its stability and expression, thereby upregulating lipogenic enzymes. Treatment with Remodelin, a NAT10-specific inhibitor, effectively ameliorates liver steatosis and dyslipidemia in a preclinical mouse model. Conclusions: Our findings indicate that NAT10 could regulate lipid metabolism in MASLD and MASH by stabilizing Srebp-1c mRNA and upregulating lipogenic enzymes. This study highlights the role of NAT10 and RNA acetylation in the pathogenesis of MASLD and MASH. Thus, our findings suggest a promising new therapeutic approach, such as the use of NAT10 inhibitor, for treating metabolic liver disease.

Objective: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC. Methods: Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients. Results: Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2−/− male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence. Conclusions: This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA. N-acetyltransferase 10 (NAT10) has not been fully explored in MASLD and MASH. The clinical relevance of NAT10 was evaluated based on its expression in various mouse and human models of MASLD and MASH. Acetylated RNA immunoprecipitation sequencing and mRNA stability assays were used to explore the role of NAT10 in regulating ac4C modification and expression of target genes. Genetically engineered mice were employed to investigate the role of NAT10 in MASLD and MASH progression. Hepatic NAT10 expression was significantly increased in multiple mice and humans of MASLD and MASH. Genetic knockout of NAT10 protected mice from diet-induced hepatic steatosis and steatohepatitis, whereas overexpression of NAT10 exacerbated high-fat-diet-induced liver steatosis. Mechanistically, NAT10 binds to Srebp-1c mRNA, promoting its stability and expression, thereby upregulating lipogenic enzymes. Treatment with Remodelin, a NAT10-specific inhibitor, effectively ameliorates liver steatosis and dyslipidemia in a preclinical mouse model. Our findings indicate that NAT10 could regulate lipid metabolism in MASLD and MASH by stabilizing Srebp-1c mRNA and upregulating lipogenic enzymes. This study highlights the role of NAT10 and RNA acetylation in the pathogenesis of MASLD and MASH. Thus, our findings suggest a promising new therapeutic approach, such as the use of NAT10 inhibitor, for treating metabolic liver disease. [Display omitted] • Identification of NAT10 as a regulator in MASLD/MASH, revealing potential therapeutic targets for chronic liver diseases. • Unveiling the role of ac4C in regulating mRNA stability, highlighting its impact on hepatic lipid metabolism. • Demonstration of elevated NAT10 expression in MASLD mouse models and patients, correlating with disease severity. • Mechanistic insights into the function of NAT10 in promoting lipid accumulation through binding to Srebp-1c mRNA. • Remodelin, a NAT10 inhibitor, improves liver steatosis and dyslipidemia in a preclinical mouse model. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC. Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients. Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2−/− male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence. This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients. [Display omitted] • SphK2 deletion protects male mice from MASH-driven HCC and promotes it in female mice. • SphK2 deficiency reduces p62 only in obese male mice and increased p62 correlates with poorer survival in male HCC patients. • High SphK2 expression in male HCC patients is associated with poor differentiation status and increased cancer recurrence. • SphK2 regulates HCC sexual dimorphism. [ABSTRACT FROM AUTHOR]