Frontiers in endocrinologyOct 10, 2026

Metabolic-related fatty liver disease: updating its definition and new treatment approaches

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 11, 2026

Abstract

Renaming non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD) reflects a shift in understanding the condition as a systemic metabolic disorder.

Oxidative stress, chronic low-grade inflammation, and mitochondrial dysfunction are interconnected factors that may drive the progression from simple fat accumulation in the liver to inflammation and scarring.
Lean MAFLD affects 20-40% of individuals with normal body mass index, suggesting that standard obesity-focused screening may miss many cases.
Extrahepatic complications, such as subclinical cardiovascular injury and type 2 diabetes-associated liver cancer, are key contributors to mortality in individuals with MAFLD.
The approval of resmetirom in March 2024 and promising results from new therapies highlight a shift towards more effective treatment options beyond lifestyle changes.
The bidirectional communication between the liver and adipose tissue, influenced by micronutrient levels, offers a new perspective on the disease's underlying mechanisms.

Simplified

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.

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Metabolic-related fatty liver disease: updating its definition and new treatment approaches

Abstract

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