Untargeted Metabolomics Reveals Metabolic Reprogramming Linked to HCC Risk in Late Diagnosed Tyrosinemia Type 1

<b>Background/Objectives</b>: Tyrosinemia type 1 (HT-1) is a treatable inherited disorder characterized by disrupted tyrosine metabolism, leading to severe liver, renal, and occasionally neurological dysfunction. Early diagnosis by newborn screening markedly reduces the risk of hepatocellular carcinoma (HCC), the most serious complication. A deeper understanding of HT-1 pathophysiology is necessary to prevent disease complications and improve diagnostic and therapeutic strategies. This study explored the untargeted serum metabolomic profiles of HT-1 patients. <b>Methods</b>: High-resolution untargeted metabolomics coupled with liquid chromatography was applied for serum analysis of 16 late-diagnosed Chilean HT-1 patients on nitisinone (NTBC) therapy and 16 age- and sex-matched controls. The statistically significant up- and down-regulated features were used for annotation and association with different metabolic pathways. <b>Results</b>: Untargeted metabolomics revealed 1066 features significantly changed in HT-1 patients. Increased metabolites included aromatic compounds, medium- and long-chain acyl-carnitines, bile acids (prevalently taurine-conjugated), indole-based compounds, modified nucleosides and nucleobases. Decreased metabolites were mainly related to lipid class, including lysophosphatidylcholines, lysophosphatidic acids, long-chain fatty acids, and acylglycerols. <b>Conclusions</b>: Untargeted metabolomics showed perturbation of tyrosine- and tryptophan-related pathways and described a novel HT-1 metabolomic pattern demonstrating net dysregulation of lipid and bile acid metabolism in NTBC-treated patients with delay diagnoses. Increased acylcarnitines, taurine-conjugated bile acids, modified nucleobases, and reduced lysophosphatidylcholines overlap with the metabolomic pattern previously reported in Wnt/β-catenin-associated HCC. Although direct mechanistic link cannot be established in this study, these alterations may reflect persistent disease-related metabolic adaptations and warrant further investigation to clarify their potential relevance with long-term complications.