Elucidating Synovial Pathophysiology in Osteoarthritis: Identification of Ferroptosis and Lipid Metabolism Signatures

Background: Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by cartilage degradation, synovial inflammation, and subchondral bone remodeling. Synovial dysregulation is known to accelerate OA progression, and recent studies suggest that ferroptosis in synovial cells may be a key contributor. However, the underlying mechanisms remain unclear. This study aimed to investigate the roles of ferroptosis and lipid metabolism in OA using bioinformatics to identify potential biomarkers and therapeutic targets.
Methods: We analyzed publicly available gene expression datasets (GSE12021, GSE55235, and GSE55457) to identify genes associated with ferroptosis and lipid metabolism. Key genes were pinpointed using ssGSEA, WGCNA, and diagnostic model construction. Further analyses included transcription factor and small molecule predictions, molecular docking, and immune infiltration assessment via CIBERSORT. To validate our findings, we employed a mouse OA model induced by medial meniscus destabilization surgery and performed RT-PCR on synovial tissue from human OA patients.
Results: Our analyses identified UGCG, SLC2A14, JUN, and FASN as key OA-related genes. RT-PCR validation on human OA synovial tissue confirmed their reduced expression, aligning with the microarray data. Histological examination of OA mouse synovium revealed altered ferroptosis markers, specifically downregulated GPX4 and upregulated ACSL4, providing direct evidence linking ferroptosis to OA progression.
Conclusions: This study underscores the critical role of synovial dysregulation and ferroptosis in OA pathophysiology. We identified UGCG, SLC2A14, JUN, and FASN as promising potential biomarkers and therapeutic targets. Further research is necessary to fully elucidate their complex interactions and precise mechanisms in OA.