Pyrimidinetrione benzodioxol ameliorates MAFLD-induced liver tumorigenesis and mood disorders in mice

The Western diets (WD) induced metabolic dysfunction-associated fatty liver disease (MAFLD) has become a major clinical burden. No pharmacological agent has been approved to treat MAFLD-induced liver cancer and systemic symptoms. In this study, mice were fed a WD combined with a CCl4 injection for 24 weeks to induce steatohepatitis, fibrosis, and liver cancer. The molecular and therapeutic effects of barbituric acid derivative pyrimidinetrione benzodioxol (BA-5) were evaluated. BA-5 treatment decreased lipids accumulation and inflammatory response through upregulating beta-oxidation genes. Furthermore, WD+CCl4-impaired detoxification and antioxidant genes were restored by BA-5. During fibrogenesis, BA-5 treatment reduced the collagen deposition in WD+CCl4 exposed mice. At the stage of hepatocarcinogenesis, BA-5 blocked the AKT/rpS6-mediated proliferation and reduced HCC markers. Notably, WD-induced anxiety- and depression-like behaviors were significantly improved in BA-5-treated mice. Although delayed BA-5 treatment showed a modest therapeutic effect, early BA-5 intervention serves as a promising agent for addressing metabolic deterioration-induced liver tumorigenesis.