Mechanism of RORα in promoting osteoarthritis through p53 deubiquitination-mediated chondrocyte ferroptosis

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage loss, in which iron dysregulation and ferroptosis contribute to disease progression. Here, we investigated the role of the RORα-p53 axis in regulating chondrocyte ferroptosis during OA. Transcriptomic analysis and experimental models revealed activation of ferroptosis and iron imbalance in OA cartilage, while pharmacological inhibition of ferroptosis alleviated cartilage damage. We identified p53 as a key mediator promoting ferroptotic signaling in chondrocytes and demonstrated that retinoic-acid-related orphan receptor alpha (RORα) acts upstream by stabilizing p53. Mechanistically, RORα recruits the deubiquitinase HAUSP to inhibit p53 ubiquitination, thereby enhancing ferroptotic responses. These findings define a regulatory pathway linking RORα to p53-dependent ferroptosis and cartilage degeneration and provide a potential molecular target for disease-modifying OA therapy.