Metabolomic Signatures of MASLD Identified by the Fatty Liver Index Reveal Gamma-Glutamyl Cycle Disruption and Lipid Remodeling

BACKGROUND/OBJECTIVES: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder worldwide and a key driver of cardiometabolic complications. Despite its growing burden, the underlying metabolic perturbations remain incompletely understood. The Fatty Liver Index (FLI) provides a validated non-invasive tool for stratifying MASLD in large-scale and clinical studies. METHODS: = 55) with balanced age, sex, and BMI. Untargeted serum metabolomics was performed. Differential metabolite profiles were identified using linear regression adjusted for covariates and validated by multivariate modeling. Functional enrichment analyses were conducted to highlight perturbed metabolic pathways. RESULTS: Metabolomic profiling revealed distinct metabolic signatures: the MASLD group was characterized by elevated glutamate and phospholipids, while the control group showed enrichment of gamma-glutamyl amino acids, plasmalogens, and sphingomyelins. CONCLUSIONS: This contrasting pattern reflects disruption of the gamma-glutamyl cycle and consistent depletion of antioxidant plasmalogen species, suggesting impaired redox homeostasis and lipid remodeling as hallmarks of MASLD pathogenesis. These findings provide a foundation for future research into targeted metabolic biomarkers and therapeutic strategies. Longitudinal and mechanistic studies are warranted to determine causal relationships and clinical utility.