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

ABSTRACT: 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-defi

SUBMITTER: Hoque MM 

PROVIDER: S-EPMC12870473 | biostudies-literature | 2026 Mar

REPOSITORIES: biostudies-literature