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. <i>In vitro</i> 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.