Targeted inhibition of hepatic de novo ceramide synthesis ameliorates MASH.

ABSTRACT: Increasing evidence implicates ceramides in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). However, the therapeutic potential of liver-targeted ceramide lowering remains unclear. In this study, we demonstrate that elevated ceramide levels in MASH patients and mouse models are closely associated with the activation of hepatic de novo ceramide synthesis. The analysis of human hepatic single-nucleus RNA sequencing (snRNA-seq) data revealed predominant up-regulation of SPTLC2, which encodes a subunit of the rate-limiting enzyme in the de novo ceramide synthesis pathway, in hepatocytes. By targeted inhibition of SPTLC2 with lipid nanoparticle-mediated siRNA delivery to hepatocytes, we reduced both hepatic and circulating ceramide levels. This intervention su

SUBMITTER: Yu X 

PROVIDER: S-EPMC12466852 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature