# GalNAc-conjugated siRNA targeting C/EBPβ reverses metabolic dysfunction and restores liver homeostasis in a murine MASLD model

## TL;DR

A new siRNA therapy targeting C/EBPβ improves liver health and metabolism in mice with a liver disease linked to metabolic dysfunction.

## Contribution

GalNAc-conjugated siRNA targeting C/EBPβ is shown to reverse metabolic dysfunction and liver damage in a MASLD model.

## Key findings

- GalNAc-siCEBPβ reduced liver steatosis and improved metabolic parameters in mice on a high-fat diet.
- The therapy restored liver function markers without causing hepatotoxicity.
- C/EBPβ silencing occurred with high efficiency both in vitro and in vivo.

## 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.

This preclinical study demonstrates that GalNAc-mediated delivery of C/EBPβ siRNA silences a key transcriptional driver of MASLD, resulting in multi-faceted therapeutic benefits. These include steatosis reduction, systemic metabolic improvements, and a restoration of hepatic function (synthetic and detoxification), offering a promising therapeutic strategy for clinical development in advanced liver stage patients.