Identifying serum essential amino acid patterns protective against the incidence and conducive to the recovery of metabolic dysfunction–associated steatotic liver disease: a prospective cohort study

While circulating essential amino acids (EAAs) have been linked to metabolic dysfunction–associated steatotic liver disease (MASLD), the serum EAA pattern favorably associated with MASLD incidence and recovery remains unclear. We aimed to identify an EAA pattern beneficially associated with MASLD outcomes and explore its dietary, lifestyle, and metabolic correlates. Data were derived from the Guangzhou Nutrition and Health Study (GNHS), which included five visits over 12 years. MASLD was assessed from follow-ups 1 to 4 but not at baseline. The discovery cohort included 867 participants with targeted metabolomics available at baseline and follow-ups 2–4. MASLD-related EAA patterns were derived from averaged metabolite levels. The identified EAA pattern was validated in 1,623 additional GNHS participants and externally in 481,982 UK Biobank participants. Dietary and lifestyle factors associated with the pattern, as well as related metabolites and pathways, were further explored. An EAA pattern characterized by higher methionine and threonine but lower valine, leucine, and isoleucine was associated with lower MASLD incidence (standardized hazard ratio [95% CI]: 0.61 [0.51–0.73]) and greater recovery (2.06 [1.67–2.53]) in the discovery cohort, with consistent associations in validation cohorts. Thirteen metabolites related to this EAA pattern, including key tricarboxylic acid (TCA) cycle intermediates (pyruvic acid, isocitric acid, and oxoglutaric acid), may partly account for the EAA–MASLD association ( P < 0.05). A healthy diet and lifestyle were positively associated with the favorable EAA pattern. A serum EAA pattern featuring higher methionine and threonine and lower branched-chain amino acids was associated with reduced MASLD risk and enhanced recovery, may partly be accounted for by metabolites implicating TCA cycle metabolism. This pattern may serve as a candidate circulating metabolic signature related to MASLD outcomes and may inform future nutritional and lifestyle intervention studies, although its clinical utility requires further validation.