Metabolic dysfunction-associated fatty liver disease: redefining the conceptual framework from nomenclature to...

The renaming of non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD), and subsequently to metabolic dysfunction-associated steatotic liver disease (MASLD), signals a paradigm shift that repositions hepatic steatosis as a systemic metabolic disorder rather than a diagnosis by exclusion. This review synthesizes the evidence supporting the nomenclature transition, examines the pathogenic mechanisms driving disease progression, evaluates the clinical implications of the lean MAFLD phenotype, and surveys the evolving therapeutic landscape. Oxidative stress, chronic low-grade inflammation, and mitochondrial dysfunction form an interconnected network propelling the trajectory from simple steatosis to steatohepatitis and fibrosis. The bidirectional liver-adipose tissue communication axis, modulated by micronutrient homeostasis, has emerged as an integrative framework for understanding disease pathobiology. Lean MAFLD, present in 20-40% of affected individuals despite normal body mass index, challenges obesity-centered screening approaches and underscores the necessity of metabolic phenotyping in routine clinical practice. Extrahepatic complications-particularly subclinical cardiovascular injury, type 2 diabetes-associated hepatocellular carcinoma, and cardiomyopathy-remain the principal causes of death in this population. The regulatory approval of resmetirom in March 2024, together with promising phase II data on incretin-based therapies, FGF21 analogs, and PPAR modulators, has begun to reshape a therapeutic field that had long relied on lifestyle modification alone. We also discuss the gut-liver axis, genetic predisposition, economic burden, and multidisciplinary management models that together define the contemporary understanding of this disease. This review integrates these developments and identifies key gaps warranting further investigation.