Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a key hepatic manifestation of obesity and systemic metabolic dysfunction and is a leading cause of chronic liver disease worldwide. Obesity-driven mechanisms, including adipose tissue dysfunction, insulin resistance and increased free fatty acid flux to the liver, promote ectopic lipid accumulation and lipotoxic injury. These processes trigger mitochondrial and endoplasmic reticulum stress, inflammation, immune activation and disturbances in the gut-liver axis, driving disease progression from simple steatosis to metabolic dysfunction-associated steatohepatitis, fibrosis and cirrhosis. MASLD is a highly heterogeneous condition, with differences in fat distribution, body composition and genetic susceptibility giving rise to distinct clinical phenotypes, including lean and non-lean MASLD, which have important implications for disease risk, progression and therapeutic response. Clinical outcomes are determined primarily by fibrosis stage, which represents the strongest predictor of liver-related and all-cause mortality, underscoring the importance of early disease recognition and risk stratification. Therapeutic strategies, therefore, increasingly target upstream metabolic drivers rather than hepatic steatosis alone. Lifestyle interventions remain foundational but are often limited by challenges in long-term adherence. Pharmacologic therapies, particularly incretin-based agents such as glucagon-like peptide-1 receptor agonists and dual incretin agonists, as well as bariatric and endoscopic metabolic procedures, have demonstrated substantial metabolic and hepatic benefits. Recognition of disease heterogeneity supports phenotype-guided approaches that integrate metabolic risk, adiposity, body composition and fibrosis assessment to personalise treatment strategies and improve long-term outcomes across the MASLD spectrum.
Keywords: MASLD; fibrosis; incretin therapies; insulin resistance; obesity; phenotype‐guided therapy.
Metabolic dysfunction–associated steatotic liver disease (MASLD is one of the most common chronic liver conditions worldwide and is closely linked to the global rise in obesity. It occurs when fat builds up in the liver due to problems related to metabolism, such as excess body weight, diabetes, and high blood pressure. In this review, we explain how excess body fat, especially fat stored around internal organs, affects the liver. When the body cannot properly store or use energy, fat can accumulate in the liver and cause damage. Over time, this can lead to inflammation, scarring (fibrosis), and in severe cases, cirrhosis or liver cancer. Importantly, not all individuals with MASLD are the same. Some people develop the disease even without being overweight, due to differences in body composition, muscle mass, or genetic factors. This means that body weight alone does not fully explain the risk of liver disease. Treatment focuses on improving overall metabolic health rather than just targeting the liver. Lifestyle changes such as diet and exercise are essential, but can be difficult to maintain. New medications, especially those that help regulate appetite and improve metabolism, have shown promising results in reducing liver fat and improving liver health. In some cases, weight‐loss procedures may also be considered. Overall, this review highlights that MASLD is not just a liver disease, but a complex condition involving multiple systems in the body. Understanding these differences between patients can help doctors choose more personalized and effective treatments.
© 2026 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.