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Life sciences · Journal article
Journal of Obesity & Metabolic Syndrome · October 23, 2026
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Background: Although emerging classification systems address the pathophysiological heterogeneity of metabolic dysfunction-associated steatotic liver disease (MASLD), the implications of these subtypes for treatment responses remain unclear.We systematically evaluated three phenotyping frameworks for stratifying responses to lifestyle management.Methods: This prospective observational cohort study included 618 patients with MASLD who received 48 weeks of guideline-based lifestyle management.The classification systems assessed were metabolic clusters-mild obesity/dyslipidemia-associated MASLD (MODM), age-related MASLD (AM), severe insulin resistance-associated MASLD, high lipoprotein(a)-associated MASLD (HLPAM), and severe mixed hyperlipidemia-associated MASLD (SMHLM); hepatic and cardiometabolic traits (control, liver-specific, and cardiometabolic); and biochemical patterns (hepatocellular, mixed, and cholestatic).The primary endpoints were responses in magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) (≥30% relative liver fat reduction), alanine aminotransferase (ALT) (≥17 IU/L decrease), and liver stiffness measurements (LSM) (≥1-stage improvement in the LSM-defined fibrosis stage).Results: Metabolic clusters demonstrated significantly greater temporal stability than the hepatic and cardiometabolic trait and biochemical pattern systems (62.8% vs. 56.6% vs. 53.4%,P=0.003).The HLPAM cluster demonstrated an attenuated MRI-PDFF response (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.15 to 0.79), while the AM cluster showed a lower ALT response (OR, 0.33; 95% CI, 0.18 to 0.62), and the MODM cluster displayed a superior LSM response compared to the others (all P<0.05).Moreover, the liver-specific cluster showed better MRI-PDFF, ALT, and LSM responses than the control cluster.However, biochemical patterns selectively stratified ALT responses, with the hepatocellular pattern demonstrating a greater response than the mixed and cholestatic patterns.Conclusion: Metabolic cluster-based MASLD subtypes exhibited differential responses to lifestyle management, supporting the integration of metabolic subtyping into clinical algorithms to optimize management.