Liver-specific delivery of MDM2 antisense oligonucleotides counteracts diet-induced metabolic-dysfunction-associated steatotic liver diseases.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of pathogenic conditions ranging from steatosis, inflammation, and fibrosis with limited treatment options. We previously demonstrated an upregulation of hepatic murine double minute 2 (MDM2) in human subjects with MASLD. Genetic deletion of hepatic MDM2 and pharmacological inhibition of systemic MDM2 improves steatosis and fibrosis in MASLD mouse models. In this study, we further developed and investigated the therapeutic potential of a hepatocyte-specific triantennary N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide targeting MDM2 (GalNAc-Mdm2ASO) in two distinct dietary-induced mouse models of MASLD: a high-fat-high-cholesterol (HFHC) diet and a choline-deficient, L-amino-acid-defined, high-fat diet (CDAHFD). In the HFHC-induced MASLD model, GalNAc-Mdm2ASO not only alleviated liver injury, steatosis, and fibrosis but also improved obesity-related insulin resistance and hyperlipidemia. The hepatoprotective effects of GalNAc-Mdm2ASO treatment were associated with a reduced accumulation of hepatic cholesterol, diacylglycerol, and ceramide, which are known to trigger MASLD. In CDAHFD-induced MASLD mouse model, GalNAc-Mdm2ASO significantly mitigated hepatic inflammation, cholesterol accumulation, and fibrosis but not triglyceride accumulation. Overall, we prove hepatic inhibition of MDM2 using GalNAc-Mdm2ASO as a promising therapeutic agent for MASLD in two rodent models with distinct pathogenesis.