Mechanism of RORα in Promoting Osteoarthritis through p53 Deubiquitination-Mediated Chondrocyte Ferroptosis

This study elucidates the role of the RORα–p53 axis in osteoarthritis (OA) pathogenesis via chondrocyte ferroptosis. The transcriptomic analysis of OA chondrocyte revealed pronounced iron dysregulation and upregulated ferroptosis markers. In a mouse OA model, the iron chelator deferoxamine attenuated cartilage damage, confirming ferroptosis's pathogenic role. We found that p53 expression was elevated in OA, promoting chondrocyte ferroptosis, while its inhibition restored antioxidant defenses. Retinoic acid-related orphan receptor alpha (RORα) acted as an upstream regulator; its overexpression exacerbated OA, whereas chondrocyte-specific knockout ameliorated cartilage damage by suppressing ferroptosis. Mechanistically, RORα stabilizes p53 by recruiting the deubiquitinase HAUSP, amplifying the ferroptotic cascade. Our findings demonstrate that the RORα–p53 axis is a novel pathogenic mechanism driving ferroptosis-mediated cartilage degeneration in OA, representing a promising therapeutic target.