Targeted inhibition of hepatic de novo ceramide synthesis ameliorates MASH
Year: 2025
Type: article
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 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 Sptlc2 as a promising therapeutic target for MASH.
Source: Science Advances
Authors: Xiaodong Yu, Chenyuan Huang, Martijn Evers, Jingjing Liu, Hui Jun Ting, Sitong Zhang, Suet Yen Chong, Michelle Siying Tan, Siyu Wang, Nilofer Sayed, Liang Gao, Mark D. Muthiah, Gwyneth S. T. Soon, Aileen Wee, Edward Kai-Hua Chow, Natalie Jun Hui Soh, Giorgia Pastorin, Victor C. Yu, Bin Liu, Yock Young Dan, Federico Torta, Raymond Schiffelers, Gert Storm, Jiong-Wei Wang
Institutions: National University of Singapore, University Medical Center Utrecht, Yangzhou University, Duke-NUS Medical School, Life Sciences Institute, National University Hospital, National University Health System, Cancer Science Institute of Singapore, Zhengzhou University, Fifth Affiliated Hospital of Zhengzhou University, Utrecht University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W4414579171