Nutrigenomics of fat-soluble vitamins and micronutrients in hepatocyte lipotoxicity and MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent liver disorder deriving from the chronic exposure to hepatocyte steatosis and its lipotoxicity effects, as mitochondrial dysfunction, overactivation of stress response and inflammatory genes, and cell death signaling. Genomics and post-genomic disciplines as nutrigenomics – the study of the interaction between the genome and diet/nutrients and its health effects – offer unprecedent opportunities in steatotic liver disease characterization, precision diagnostics, and treatment, particularly through lifestyle modifications and nutritional interventions. In this context, fat-soluble vitamins (FSV) and other lipid nutrients as omega-3 fatty acids, have shown cytoprotective properties and molecular effects useful in modulating key steps of the hepatocellular lipotoxicity process, such as lipid biosynthesis, lipid peroxidation, inflammatory gene activation and cell death. Applications of nutrigenomics also include drug discovery and preclinical studies to explore therapeutic mechanisms and efficacy of vitamin products through the criteria of precision nutrition. This review discusses current evidence on hepatocyte lipotoxicity and its nutrigenomic exploration to identify disease mechanisms, nutritional defects and opportunities of intervention with FSV and other lipid factors as omega-3 fatty acids. Their properties, limitations, and potential for translation in the prevention and clinical management of MASLD, are also critically evaluated.