Untargeted Metabolomics Reveals Dysregulation of Glycine- and Serine-Coupled Metabolic Pathways in an ALDH1L1-Dependent Manner In Vivo

<b>Background:</b> ALDH1L1 plays a crucial role in folate metabolism, regulating the flow of one-carbon groups through the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO₂ in a NADP⁺-dependent reaction. The downregulation of ALDH1L1 promotes malignant tumor growth, and silencing of ALDH1L1 is commonly observed in many cancers. In a previous study, <i>Aldh1l1</i> knockout (KO) mice were found to have an altered liver metabotype, including significant alterations in glycine and serine. Serine and glycine play crucial roles in pathways linked to cancer initiation and progression, including one-carbon metabolism. <b>Objective/Methods:</b> To further investigate the metabolic role of ALDH1L1, an untargeted metabolomic analysis was conducted on the liver and plasma of both KO and wild-type (WT) male and female mice. Since ALDH1L1 affects glycine- and serine-coupled metabolites and metabolic pathways, correlation analyses between liver glycine and serine with other liver or plasma metabolites were performed for both WT and KO mice. Significantly correlated metabolites were input into MetaboAnalyst 5.0 for pathway analysis to uncover metabolic pathways coupled with serine and glycine in the presence or absence of ALDH1L1 expression. <b>Results:</b> This analysis showed substantial alterations in pathways associated with glycine and serine following ALDH1L1 loss, including the amino acid metabolism, antioxidant pathways, fatty acid oxidation, and vitamin B5 metabolism. These results indicate the glycine- and serine-linked metabolic reprogramming following ALDH1L1 loss to support macromolecule biosynthesis and antioxidant defense. Additional research is required to further explore the correlation between specific alterations in these pathways and tumor growth, as well as to identify potential dietary interventions to mitigate the detrimental effects of ALDH1L1 loss.