Targeted inhibition of hepatic de novo ceramide synthesis ameliorates MASH
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 <i>SPTLC2</i>, 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 suppressed hepatic lipid uptake and lipogenesis, thereby alleviating MASH progression. Therapeutic efficacy was demonstrated in an 8-week methionine-choline-deficient diet-induced MASH model and validated in a 1-year choline-deficient high-fat diet-induced MASH model. Our findings highlight hepatocyte <i>Sptlc2</i> as a promising therapeutic target for MASH.
Authors
- Giorgia Pastorin (ORCID: https://orcid.org/0000-0002-2568-0626)
- Michelle Siying Tan
- Edward Kai‐Hua Chow (ORCID: https://orcid.org/0000-0002-3075-1898)
- Raymond M. Schiffelers (ORCID: https://orcid.org/0000-0002-1012-9815)
- Yock Young Dan (ORCID: https://orcid.org/0000-0002-7546-2117)
- Hui Jun Ting (ORCID: https://orcid.org/0000-0002-5054-6680)
- Gwyneth Shook Ting Soon (ORCID: https://orcid.org/0000-0001-5318-9327)
- Suet Yen Chong (ORCID: https://orcid.org/0000-0002-3627-4025)
- Nilofer Sayed (ORCID: https://orcid.org/0000-0002-9650-0549)
- Mark Dhinesh Muthiah (ORCID: https://orcid.org/0000-0002-9724-4743)
- Victor C. Yu (ORCID: https://orcid.org/0000-0003-3270-4734)
- Federico Torta (ORCID: https://orcid.org/0000-0001-7545-7484)
- Chenyuan Huang (ORCID: https://orcid.org/0000-0002-1812-7283)
- Jiong‐Wei Wang (ORCID: https://orcid.org/0000-0001-7986-6082)
- Natalie Jun Hui Soh (ORCID: https://orcid.org/0000-0002-7904-9880)
- Martijn J.W. Evers (ORCID: https://orcid.org/0000-0001-6112-0717)
- Jingjing Liu (ORCID: https://orcid.org/0000-0002-8153-6653)
- Siyu Wang (ORCID: https://orcid.org/0009-0003-1854-898X)
- Bin Liu (ORCID: https://orcid.org/0000-0002-0956-2777)
- Sitong Zhang (ORCID: https://orcid.org/0000-0002-1613-4682)
- Aileen Wee
- Liang Gao (ORCID: https://orcid.org/0000-0003-3700-1069)
- Xiaodong Yu
- Gert Storm
Institutions
- National University of Singapore (SG)
- University of Applied Sciences Utrecht (NL)
- Utrecht University (NL)
- Zhengzhou University (CN)
- Henan Tianguan Group (China) (CN)
- National University Cancer Institute, Singapore (SG)
- Fifth Affiliated Hospital of Zhengzhou University (CN)
- National University Hospital (SG)
- Signature Research (United States) (US)
- Yangzhou University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1126/sciadv.adx2681
- Citations
- 5
- Primary Topic
- Ginger and Zingiberaceae research
- Type
- article
- Field-Weighted Citation Impact
- 7.79