GalNAc-conjugated siRNA targeting C/EBPβ reverses metabolic dysfunction and restores liver homeostasis in a murine MASLD model
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
CCAAT/enhancer-binding protein beta (C/EBPβ) is a master regulator of hepatic metabolism, inflammation, and fibrosis, making it an attractive but underexploited target for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we demonstrate that GalNAc-conjugated small interfering RNA (siRNA) targeting C/EBPβ (GalNAc-siCEBPβ) significantly improves liver function and metabolic parameters in a high fat diet (HFD) murine model. In vitro, GalNAc-siCEBPβ achieved dose-dependent C/EBPβ mRNA silencing (∼80% knockdown at 0.1 μM) in primary mouse hepatocytes. In vivo, subcutaneous administration (10 mg/kg) reduced hepatic C/EBPβ expression by 45% (p < 0.01), concomitant with a marked reduction in liver steatosis and improved metabolic profile (15% less weight gain, 20% lower glucose, 25% reduced triglycerides), and restored liver function (18% higher albumin, 22% lower bilirubin)—all without hepatotoxicity (ALT/AST unchanged). Notably, these effects occurred despite continued HFD feeding, suggesting disease-modifying potential. By leveraging the precision of RNAi and hepatocyte-specific GalNAc delivery, GalNAc-siCEBPβ addresses key limitations of current MASLD therapies by targeting both metabolism and fibrosis. Our findings support clinical translation for MASLD and its complications, including hepatocellular carcinoma.
Date Issued
2026-03-12
Date Acceptance
2026-02-09
Citation
Molecular Therapy: Nucleic Acids, 2026, 37 (1), pp.102865-102865
ISSN
2162-2531
Publisher
Elsevier
Start Page
102865
End Page
102865
Journal / Book Title
Molecular Therapy: Nucleic Acids
Volume
37
Issue
1
Copyright Statement
© 2026 The Authors. Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41783787
PII: S2162-2531(26)00036-3
Subjects
C/EBPβ
CCAAT/enhancer-binding protein beta
MASLD
hepatic steatosis
liver function
metabolic syndrome
metabolic-dysfunction-associated steatotic liver disease
pre-clinical model
siRNA therapeutics
Publication Status
Published
Coverage Spatial
United States
Article Number
102865
Date Publish Online
2026-02-11