Increased 1-deoxysphingolipids caused by an altered plasma alanine to serine ratio are associated with metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) (formerly Non-Alcoholic Fatty Liver Disease, NAFLD) encompasses a spectrum of metabolic disorders ranging from isolated steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). In this study, we investigated metabolic changes in MASLD by analysing plasma lipidomics and metabolomics profiles from 315 biopsy-characterized patients. We observed significant alterations in alanine/serine (ala/ser) ratio, 1-deoxysphingolipids, alanine aminotransferase (ALT), and waist/hip ratio (whr) between patients with and without MASH. These findings highlight a close interplay between amino acid metabolism and sphingolipid biosynthesis in MASLD progression. The shift in ala/ser ratio particularly distinguished non-MASH from borderline MASH patients, suggesting that early metabolic disruptions precede overt liver damage. Additionally, elevated branched-chain and aromatic amino acids correlated with steatosis severity, reinforcing the central role of amino acid dysregulation in MASLD. While a simple model combining ALT, ala/ser ratio, and whr showed some potential to support risk stratification, the primary significance of our findings lies in the mechanistic insights into metabolic dysfunction. In conclusion, this study emphasizes the importance of metabolic network alterations in MASLD and points toward future opportunities for both mechanistic research and the development of supportive diagnostic strategies.