Beyond Fat: Reframing MASLD Through Genetics, Clonal Biology, and Precision Hepatology

Metabolic dysfunction-associated steatotic liver disease (MASLD) has traditionally been conceptualized as a predominantly metabolic disorder driven by obesity and insulin resistance. However, recent advances in human genetics have revealed a more complex picture that encompasses germline susceptibility variants, protective loss-of-function alleles, polygenic risk models, and somatic clonal evolution. Since the discovery of PNPLA3 (patatin-like phospholipase domain-containing 3) I148M, multiple loci—including TM6SF2, MBOAT7, GCKR, HSD17B13, MTARC1, GPAM, and CIDEB—have substantially expanded the mechanistic understanding of disease heterogeneity and hepatocellular vulnerability. Recent studies integrating partitioned polygenic risk scores and unsupervised phenotypic clustering suggest that MASLD may be organized into at least two predominant subtypes: a liver-specific subtype characterized by intrinsic hepatocellular susceptibility, and a cardiometabolic subtype associated with systemic metabolic dysfunction and increased cardiovascular risk. Analyses of cirrhotic liver tissue have, in turn, demonstrated somatic clonal expansion of hepatocytes harboring adaptive metabolic mutations, adding an evolutionary dimension to advanced disease. On this basis, we propose an integrated LS/CM/C framework encompassing liver-specific (LS), cardiometabolic (CM), and clonal (C) components. This model offers a conceptual structure that links germline genetics, metabolic heterogeneity, somatic adaptation, and emerging pharmacogenomic strategies. The recent development of genotype-directed therapies targeting PNPLA3 and HSD17B13, together with the approval of resmetirom and semaglutide, further supports the transition toward biologically stratified hepatology. Although prospective validation remains necessary, the convergence of genetics, clonal biology, and targeted therapeutics suggests that MASLD is moving toward an era of precision medicine.