TLR1-Regulated Ferroptosis Gene Decreases the Occurrence of Restless Legs Syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a sensory motor neuropathy that is frequently encountered. Transcriptome analysis has revealed the role of ferroptosis in the pathogenesis of RLS. However, the role of ferroptosis in RLS and the upstream regulatory molecules governing ferroptosis remain unknown. METHODS: This study aims to explore the causal relationship and mechanisms between ferroptosis genes, upstream genes, and RLS using Mendelian Randomization (MR). This study employed two-sample MR analysis and mediation analysis, utilizing RLS GWAS data from the Finngen database, ferroptosis genes data from the decode database, and upstream genes data from the the UK Biobank Pharma Proteomics Project. A two-sample MR analysis was used to evaluate the causal relationship between the ferroptosis genes and RLS. Then, mediation analysis was conducted to explore the mediating effect of upstream genes on the relationship between expression of ferroptosis genes and RLS. RESULTS: Our study found a significant positive correlation between high expression of the FURIN gene and a reduced risk of RLS. Further exploration of upstream genes regulating ferroptosis genes revealed that these genes indirectly influence the occurrence of RLS by regulating the expression of the FURIN gene. Mediator effect analysis showed that TLR1 indirectly reduces the occurrence of RLS by regulating the expression of the FURIN gene, with the mediator effect of FURIN gene expression accounting for 17.9% of the total effect. Sensitivity analysis supported our findings, indicating high statistical robustness. CONCLUSION: This study highlights the role of TLR1 in regulating FURIN during the progression of RLS, suggesting the potential clinical application of FURIN as a therapeutic target for the early diagnosis and treatment of RLS.