Liver-targeted DGAT2 siRNA ameliorates steatosis and fibrosis in a high-fat diet-induced MASH mouse model.

Diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in hepatic triglyceride (TG) synthesis, is considered a promising therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH). Small interfering RNAs (siRNAs) targeting conserved regions of human and mouse DGAT2 mRNA were designed, synthesised and screened in vitro leading to the identification of a GalNAc-conjugated siRNA, VX093L, which mediates potent DGAT2 mRNA knockdown in both human and mouse hepatocytes and exhibits sustained hepatic DGAT2 silencing in healthy mice. In a high-fat diet (HFD)-induced MASH mouse model, the effects of VX093L (1 or 3 mg/kg, biweekly) were evaluated in comparison with the approved drug resmetirom (10 mg/kg, daily). Eight weeks of treatment with VX093L potently silenced hepatic DGAT2 (>80%, p < 0.0001), thereby inhibiting hepatic TG synthesis and significantly ameliorating hepatic steatosis. Notably, VX093L treatment also effectively attenuated fibrosis, with 1 mg/kg VX093L exhibiting greater anti-fibrotic efficacy than resmetirom, without an increase in inflammation. In conclusion, VX093L represents a promising siRNA-based therapeutic for the treatment of MASH.