Weight changes differentially impact MASLD incidence, progression and outcomes based on genetic and metabolic risk profiles

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Background & Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is driven by environmental (e.g., nutrition), metabolic and genetic factors, leading to heterogeneous subgroups with liver- vs. cardiovascular-related adverse outcomes. Weight management is crucial in MASLD and related adverse events, but the effect of weight loss on MASLD subgroups is unclear. Methods A metabolic risk group was defined by lipid accumulation product, and two MASLD subgroups (i.e., hepatic and systemic progression) were defined by polygenic risk scores. A Cox proportional model was constructed to delineate the range of weight loss in the general population and subgroups after sex stratification. Results There were 11,882 Caucasian participants without MASLD and 6,013 participants with MASLD at baseline with a median 4 years of follow-up. We identified a baseline body mass index (BMI)>26 kg/m2 from which weight loss became effective for preventing MASLD. For MASLD resolution, individuals with hepatic and systemic genetic risk require>10% weight loss to reverse steatosis and inflammation, while those in the metabolic group benefit within a broader range (about 6–15%). Weight loss appears less effective for fibrosis regression in the hepatic risk group, whereas systemic/metabolic risk groups—especially men—should aim for>7% reduction. For MASLD-related cardiovascular risk, at least 9% weight loss is generally beneficial, though genetically defined subgroups may experience limited improvement. Conclusion Weight loss can prevent and treat MASLD, and individualized weight management should be recommended according to the genetic and metabolic risk profile of individuals. Publication History Article published online: 26 January 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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