Mapping the genomic landscape of MASLD: A framework for molecular subtyping and precision hepatology

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not merely a hepatic manifestation of systemic metabolic dysregulation, but a central node and active determinant of multi-organ derangement. As a primary cause of cirrhosis and hepatocellular carcinoma, the progression to metabolic dysfunction-associated steatohepatitis (MASH) represents a critical prognostic threshold. The pathogenesis of MASLD reflects a complex genomic architecture arising from the interplay of rare high-penetrance variants, common genetic risk loci, and extrinsic modifiers. While Mendelian drivers illuminate fundamental pathways in intermediary metabolism and cellular stress, common variants account for the interindividual heterogeneity in fibrosis severity. Epigenetic modifications, mitochondrial dynamics, and host-microbiota interactions functionally bridge environmental exposures and host genomic risk. These converging biological layers-environmental clues, including microbial metabolites, to the host epigenome-establish a framework for precision risk stratification and the development of genotype-directed therapeutics tailored to specific molecular subtypes.