Iron Metabolism and Multiple Sclerosis: Unveiling the Connection

Multiple sclerosis (MS) is a prevalent chronic inflammatory disease of the central nervous system (CNS), affecting over 2 million people globally. Characterized by the formation of "plaques of sclerosis" in various CNS regions, including white and gray matter, brainstem, spinal cord, and optic nerve, MS leads to significant neurological dysfunction. The pathogenesis of MS involves complex interactions among the immune system, glial cells, and neurons, resulting in inflammatory demyelination, neuronal injury, and brain lesions.

Recent research suggests a potential link between iron metabolism disorders and the onset and progression of MS. Iron, a crucial trace metal, is involved in the metabolism of neurotransmitters and the formation of myelin. Abnormal iron deposition in the brain has been associated with both aging and MS, potentially contributing to oxidative stress and subsequent neural damage.

Methods and Materials
The study utilized publicly available databases and bioinformatics techniques for gene expression data analysis. These included differential expression analysis, weighted correlation network analysis (WGCNA), gene enrichment analysis, and logistic regression models. To establish a causal relationship between iron metabolism markers and MS, Mendelian randomization (MR) was employed.

Key Findings
1. Gene Identification and Analysis: Six genes (IREB2, LAMP2, ISCU, ATP6V1G1, ATP13A2, and SKP1) were identified as being associated with both iron metabolism and MS.
These genes demonstrated a high diagnostic value for MS, with an area under the curve (AUC) of 0.83.

2. Causal Relationships: MR analysis revealed a potential causal relationship between transferrin saturation and MS (p=2.22E-02; OR 95% CI=0.86 (0.75, 0.98)), as well as serum transferrin levels and MS (p=2.18E-04; OR 95% CI=1.22 (1.10, 1.36)).

These findings suggest that both iron deficiency and excess may influence MS risk and progression.

3. Diagnostic Model: A logistic regression model based on the identified genes showed strong diagnostic performance for MS, validated in multiple datasets.

Discussion
Iron metabolism plays a crucial role in the pathogenesis of MS. Abnormal iron deposition can lead to oxidative stress, contributing to demyelination and neuronal damage. Conversely, iron deficiency can impair oligodendrocyte function and myelin synthesis, exacerbating MS symptoms. This study highlights the dual nature of iron metabolism in MS, where both excess and deficiency can negatively impact disease progression.

The findings provide a foundation for future research into iron metabolism disorders as a therapeutic target for MS. By understanding the complex relationship between iron and MS, new treatment strategies focusing on iron homeostasis may be developed.

Conclusion
This comprehensive analysis underscores the significance of iron metabolism in MS pathogenesis. The integration of bioinformatics and MR methods has provided valuable insights into the genetic and metabolic factors influencing MS. These discoveries pave the way for further research and potential therapeutic interventions targeting iron metabolism disorders in MS.

References:
Tang C, Yang J, Zhu C, Ding Y, Yang S, Xu B, He D. (2024). Iron metabolism disorder and multiple sclerosis: a comprehensive analysis. Front. Immunol. 15:1376838. doi: 10.3389/fimmu.2024.1376838