RNA editing is a novel mechanism of action to modulate disease-associated proteins while preserving the native human gene and cellular context. Because editing oligonucleotides are sequence-specific, humanized preclinical models are important for evaluating target engagement and pharmacodynamic effects. This presentation describes a liver-humanized mouse platform generated using primary human hepatocytes. The model preserves key aspects of human liver biology, including hepatic architecture, transporter and metabolic enzyme expression, and disease-relevant genetic variation. Two applications are presented. First, NTCP-directed RNA editing is evaluated as a strategy to reduce hepatic bile acid uptake in cholestatic disease. MALDI mass spectrometry imaging is used to quantify spatial bile acid distribution across the liver and thereby assess NTCP transporter activity in vivo. Second, PNPLA3 I148M editing is evaluated in humanized mice engrafted with hepatocytes carrying the disease-associated variant and exposed to a Western diet, providing a model for genetically driven MASH.