Targeting CIDEB alleviates liver steatosis and fibrosis in mouse MASH models.

Cell death-inducing DNA fragmentation factor alpha-like effector B (CIDEB), predominantly expressed in the liver, has been identified as a protective factor against the development of metabolic dysfunction-associated steatohepatitis (MASH) when harboring loss-of-function mutations. In this study, we developed a novel GalNAc-conjugated CIDEB siRNA (GalNAc-siCIDEB) for hepatic delivery to silence CIDEB in the liver, aiming to mimic this protective effect in mouse models. In vitro efficacy screening demonstrated that the siRNA achieved robust silencing of CIDEB across multiple cell lines. In an adeno-associated virus serotype 8 (AAV8)-hCIDEB mouse model, GalNAc-siCIDEB exhibited potent and sustained silencing effect of CIDEB in the hepatocytes, with minimal off-target effects and no observed toxicity. Furthermore, in both high-fat diet-induced obese (HFD-DIO) and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced MASH mouse models, GalNAc-siCIDEB effectively reduced lipid droplet formation, suppressed inflammation, and reversed liver steatosis. Additionally, GalNAc-siCIDEB significantly reduced CDAHFD-induced fibrosis in the liver. These findings highlight hepatocyte-specific CIDEB silencing as a promising therapeutic strategy and suggest GalNAc-siCIDEB as a potential candidate for treating MASH.