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

Area of Science:

• Biomedical research
• Molecular biology
• Immunology

Background:

• Rheumatoid arthritis (RA) is a chronic autoimmune disease.
• Ferroptosis, a regulated form of cell death, is implicated in RA pathogenesis.
• Identifying specific ferroptosis-related genes (FRGs) is crucial for understanding RA and developing targeted therapies.

Purpose of the Study:

• To identify hub ferroptosis-related genes (FRGs) in rheumatoid arthritis (RA).
• To investigate the diagnostic and therapeutic potential of identified FRGs in RA.
• To explore FRGs-guided therapeutic strategies, including natural compounds, for RA treatment.

Main Methods:

• Differential expression analysis of FRGs in RA synovial tissue from the GSE12021 dataset.
• Gene Ontology and KEGG pathway analyses to identify associated signaling pathways.
• Topological analysis to identify hub genes (EGR1, CDKN1A) and evaluation of their diagnostic accuracy.
• Connectivity Map (CMap) database analysis for potential drug discovery.
• In vitro and in vivo validation of therapeutic effects.

Main Results:

• Two hub FRGs, EGR1 and CDKN1A, were identified and found to be downregulated in RA synovial tissue.
• GPx4 expression, a key ferroptosis regulator, was also decreased in RA patients.
• The natural compound withaferin-a showed significant potential as a therapeutic agent based on CMap analysis.
• In vitro and in vivo experiments confirmed the anti-arthritic effects of withaferin-a.

Conclusions:

• Ferroptosis plays a significant role in the pathogenesis of rheumatoid arthritis.
• The identified FRGs, EGR1 and CDKN1A, represent potential diagnostic and therapeutic targets for RA.
• Withaferin-a demonstrates potential as a novel therapeutic agent for treating RA.