The effects of denifanstat on hepatitis E virus replication and triggered inflammatory response

Metabolic dysfunction-associated steatotic liver disease (MASLD) is initiated by intra-cellular fatty acid accumulation, with macrophage-mediated inflammatory responses playing a pivotal role in driving disease progression. MASLD frequently coexists with viral infections, for example in the context of hepatitis E virus (HEV) infection which explores host lipid metabolism for its replication and secretion. But no targeted therapies currently exist for this complex comorbidity. Denifanstat, a fatty acid synthase (FASN) inhibitor developed for treating metabolic dysfunction-associated steatohepatitis (MASH), has shown to have antiviral activity against SARS-CoV-2 infection. In this study, we aim to assess the effects of denifanstat on HEV infection in the context of steatotic liver disease. We first employed human liver-derived primary organoids exposed to fatty acids and inoculated with HEV. Treatment with denifanstat had no major effect on HEV replication in the steatotic organoids. However, we found that denifanstat moderately inhibited viral replication in macrophages, and regulated HEV-triggered inflammatory responses. These results highlight the importance of understanding how the emerging MASH treatment may affect viral infections that coexist in patients.