Abstract
OBJECTIVE: This study aimed to investigate the role of ferroptosis-related genes and pathways in cartilage degeneration in knee osteoarthritis (KOA) and to identify potential therapeutic targets. METHODS: Integrated bioinformatics analysis of public KOA transcriptomic datasets was performed to identify differentially expressed ferroptosis-related genes. Key pathways and hub genes were further validated using a surgically-induced KOA mouse model and clinical cartilage samples through histology, immunohistochemistry, micro-CT, ELISA, western blot, and qPCR. RESULTS: Significant iron deposition, mitochondrial damage, and dysregulation of ferroptosis markers (e.g., decreased GPX4 and increased p53) were observed in KOA cartilage. Key genes such as MMP2, SPP1, MYC, and BNIP3 were identified, and pathways including mTOR and HIF-1 signaling were enriched. Experimental results consistently indicated enhanced ferroptosis and matrix degradation in both mouse and human OA samples. CONCLUSION: Ferroptosis contributes significantly to KOA progression through iron overload, lipid peroxidation, and dysregulated metabolic pathways, providing new insight for targeted therapeutic strategies.