Precision medicine in metabolic dysfunction-associated steatotic liver disease: genetics, epigenetics, and emerging therapies

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major driver of chronic liver disease and an increasingly important etiology for hepatocellular carcinoma (HCC). Despite shared metabolic risk factors, MASLD shows marked inter-individual heterogeneity in fibrosis progression, treatment response, and HCC risk, indicating that one-size-fits-all management is insufficient. This narrative review synthesizes advances in precision medicine for MASLD with emphasis on (i) genetic risk stratification (major variants such as PNPLA3 and TM6SF2, protective alleles such as HSD17B13/MARC1, polygenic risk scores (PRS), and ancestry-specific effects); (ii) functional genomics and cell biology [bulk and single-cell expression quantitative trait locus (eQTL) mapping, spatial multi-omics, and cell-state/zonation biology]; and (iii) epigenetic regulation (DNA methylation, histone modifications, and microRNA networks) linking environment to phenotype. We discuss translational implications including biomarker-enabled trial enrichment, risk-based surveillance for advanced fibrosis and HCC, and emerging therapeutics ranging from liver-directed small interfering RNA/antisense oligonucleotides to epigenetic modulators. Finally, we outline how multimodal data integration and artificial intelligence may support clinically deployable risk models and treatment selection. Collectively, the field is moving from population-based management toward individualized prevention and therapy for MASLD and its complications.

Keywords

Steatotic liver disease / precision medicine / polygenic risk score / epigenetics / eQTL

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