Exploration and validation of therapeutic molecules for rheumatoid arthritis based on ferroptosis-related genes

Aims: This study aimed to identify hub ferroptosis-related genes (FRGs) and investigate potential therapy for RA based on FRGs. Main methods: The differentially expressed FRGs in synovial tissue of RA patients were obtained from the dataset GSE12021 (GPL96). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to investigate the potential signaling pathways associated with FRGs. Hub genes were identified through topological analysis. The expression levels of these hub genes as well as their diagnostic accuracies were further evaluated. Connectivity Map (CMap) database was utilized to analyze the top 10 FRGs-guided potential drugs for RA. In vitro and in vivo experiments were carried out for further validation. Key findings: 2 hub genes among 58 FRGs were identified (EGR1 and CDKN1A), and both were down regulated in RA synovial tissue. GPx4 expression was also decreased in the RA synovial tissue. The natural compound withaferin-a exhibited the highest negative CMap score. In-vitro and in-vivo experiments demonstrated antiarthritic effects of withaferin-a. Significance: Ferroptosis participates in pathogenesis of RA, ferroptosis-related genes EGR1 and CDKN1A can be used as diagnostic and therapeutic targets for RA. Withaferin-a can be used as potential anti-arthritic treatment.