Serum Metabolomic Signatures of Iron Deficiency Anemia: An Untargeted LC‐HRMS‐Based Case–Control Study

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Abstract
Objective: Iron deficiency anemia is primarily evaluated using hematological and iron‐related parameters; however, these markers may not fully reflect the systemic metabolic consequences of impaired oxygen delivery and altered iron availability. This study aimed to characterize serum metabolomic alterations associated with iron deficiency anemia using an untargeted LC‐HRMS approach. Materials and Methods: Serum samples from 47 individuals with iron deficiency anemia and 50 healthy controls were analyzed by LC‐HRMS in positive and negative ionization modes. Data processing and metabolite annotation were performed using MassCube and MZmine workflows. Multivariate and univariate analyses, covariate‐adjusted models, metabolite set enrichment analysis, correlations with hematologic/iron indices, and internally cross‐validated exploratory ROC analyses were performed. Results: PCA showed partial separation between iron deficiency anemia and control groups, while OPLS‐DA demonstrated clearer group discrimination. Differential metabolites indicated prominent alterations in amino acid, central carbon, nitrogen‐related, and redox‐associated pathways. The principal amino‐acid/nitrogen‐related differences remained significant after adjustment for age, sex, albumin, and total protein. In the full cohort, several discriminatory metabolites correlated with hemoglobin, ferritin, and transferrin saturation, although these correlations did not remain FDR‐significant within the IDA group alone. Repeated stratified 5‐fold cross‐validation yielded a mean AUC of 0.964 for the three‐metabolite model comprising isoleucine, isonicotinic acid, and phenylalanine. Conclusion: Untargeted serum metabolomics revealed a distinct metabolic signature in iron deficiency anemia, mainly involving amino acid remodeling, central carbon metabolism, nitrogen balance, and redox‐associated pathways. These findings provide a basis for future targeted and externally validated metabolomics studies.

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