Liver-Targeted DGAT2 siRNA Ameliorates Steatosis and Fibrosis in a High-Fat Diet-Induced MASH Mouse Model.

Abstract

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, synthesized, 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-week treatment with VX093L potently silenced hepatic DGAT2 (>80%, p < 0.0001), thereby inhibiting hepatic TG synthesis, resulting in significantly ameliorating hepatic steatosis. Notably, the improvement in steatosis translated into effective attenuation of fibrosis, with 1 mg/kg VX093L exhibiting better anti-fibrotic efficacy compared to resmetirom, and this benefit was not accompanied by increased inflammation. In conclusion, VX093L represents a promising siRNA-based therapeutic for the treatment of MASH.