Identification of Key Ferroptosis-Related Genes in the Peripheral Blood of Patients with Relapsing-Remitting Multiple Sclerosis and Its Diagnostic Value

Abstract

Multiple sclerosis (MS) is a neurodegenerative disease with a complex pathogenesis. Re-lapsing-remitting multiple sclerosis (RRMS) is the most common subset of MS, accounting for approximately 85% of cases. Recent studies have shown that ferroptosis may contribute to the progression of RRMS, but the underlying mechanism remains to be elucidated. Herein, this study intended to explore the molecular network of ferroptosis associated with RRMS and establish a predictive model for efficacy diagnosis. Firstly, RRMS-related module genes were identified using weighted gene co-expression network analysis (WGCNA). Secondly, the optimal machine learning model was selected from four options: the generalized linear model (GLM), random forest model (RF), support vector machine model (SVM), and extreme gradient boosting model (XGB). Subsequently, the predictive efficacy of the diagnostic model was evaluated using receiver operator characteristic (ROC) analysis. Finally, a SVM diagnostic model based on five genes (JUN, TXNIP, NCOA4, EIF2AK4, PIK3CA) was established, and it demonstrated good predictive performance in the validation dataset. In summary, our study provides a systematic exploration of the complex relationship between ferroptosis and RRMS, which may contribute to a better understanding of the role of ferroptosis in the pathogenesis of RRMS and provide promising diagnostic strategies for RRMS patients.

Targeted RNAseq Revealed the Gene Expression Signature of Ferroptosis-Related Processes Associated with Disease Severity in Patients with Multiple Sclerosis

“…Most of the studies related to MS pathology were performed in the EAE model, animal model of MS and several types of cell models. In humans, bioinformatic analyses of ferroptosis genes in the pre-existing transcriptome datasets predominate [ 13 , 14 ]. There is a lack of studies conducted in MS patients encompassing clinical features and disease severity.…”

“…In addition, ferroptosis-related gene expression signatures to define the set of genes whose differential expression could reflect MS severity or distinguish extreme disease phenotypes, mild relapse–remitting (RR) MS and severe secondary progressive (SP) MS, have not been identified yet. Recent efforts have been made to suggest the enrichment of biological functions associated with ferroptosis, by reanalyzing the existing transcriptome data sets in MS [ 13 , 14 ]. Targeted sequencing of the particular pathway and its close regulators may provide higher sensitivity for detecting both low-abundant and less variable transcripts that could be missed by a transcriptome analysis approach.…”

“…In addition, performing de novo experimental analysis in carefully defined distinctive phenotypes increases the accuracy of finding relevant and substantial differences in gene expression. As already noted [ 14 ], the main limitation of published bioinformatic studies was a lack of the clinical features of the patients, as the consequence of the employment of publicly available data sets.…”

Ferroptosis induces detrimental effects in chronic EAE and its implications for progressive MS

“…Therefore, a key requirement for mobilizing redox active iron for ferroptosis is present in CH-EAE and SPMS. A recent study screening ferroptosis related genes in peripheral blood of RRMS cases reported down-regulation of NCOA4 [ 67 ]. This may indicate protection and promotion of remission in RRMS by preventing release of redox active iron from ferritin stores.…”