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Variation in methotrexate (MTX) efficacy represents a significant barrier to early and effective disease control in the treatment of autoimmune arthritis. We hypothesize that the utilization of metabolomic techniques will allow for an improved understanding of the biochemical basis for the pharmacological activity of MTX, and can promote the identification and evaluation of novel molecular biomarkers of MTX response. In this work, erythroblastoid cells were exposed to MTX at the physiologic concentration of 1,000 nM and analyzed using three metabolomic platforms to give a broad spectrum of cellular metabolites. MTX pharmacological activity, defined as cellular growth inhibition, was associated with an altered cellular metabolomic profile based on the analysis of 724 identified metabolites. By discriminant analysis, MTX treatment was associated with increases in ketoisovaleric acid, fructose, galactose, and 2‐deoxycytidine, and corresponding reductions in 2‐deoxyuridine, phosphatidylinositol 32:0, orotic acid, and inosine monophosphate. Inclusion of data from analysis of folate metabolism in combination with chemometric and metabolic network analysis demonstrated that MTX treatment is associated with dysregulated folate metabolism and nucleotide biosynthesis, which is in line with its known mechanism of action. However, MTX treatment was also associated with alterations in a diversity of metabolites, including intermediates of amino acid, carbohydrate, and lipid metabolism. Collectively, these findings support a robust metabolic response following exposure to physiologic concentrations of MTX. They also identify various metabolic intermediates that are associated with the pharmacological activity of MTX, and are, therefore, potential molecular biomarker candidates in future preclinical and clinical studies of MTX efficacy in autoimmune arthritis.

Metabolomic Profiling to Identify Molecular Biomarkers of Cellular Response to Methotrexate In Vitro