Abstract

Background Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by disruption of articular cartilage homeostasis, with ferroptosis of chondrocytes playing a crucial role. Cerium oxide nanoparticles (CeONPs), a class of inorganic nanozymes, exhibit potent antioxidant and anti-inflammatory properties. However, their effects on OA chondrocytes remain poorly understood. Methods: mPEG 2k -DSPE was employed to facilitate the transfer of CeONPs into the aqueous phase, resulting in PEG-CeONPs. Primary chondrocytes were isolated and subjected to erastin treatment to induce ferroptosis. The impact of PEG-CeONPs on oxidative stress, Fe 2+ concentrations, mitochondrial dysfunction, ferroptosis-associated proteins, and OA-related catabolic phenotypes was evaluated. Additionally, the involvement of NRF2 in ferroptosis and its chondroprotective effects were investigated using NRF2-siRNA. An experimental OA model was established in rats through anterior cruciate ligament transection. Results Our study demonstrated that PEG-CeONPs attenuated erastin-induced cytotoxicity and reduced oxidative stress in chondrocytes. Moreover, PEG-CeONPs inhibited erastin-induced ferroptosis and promoted collagen matrix synthesis and secretion. The protective effects of PEG-CeONPs were mediated by the NRF2 pathway, as NRF2 silencing via siRNA significantly diminished the anti-ferroptosis and chondroprotective effects of PEG-CeONPs in vitro . These findings were further validated in OA rat models, where PEG-CeONPs treatment led to a reduction in ferroptosis-related gene expression and significantly alleviated cartilage degradation. Conclusions This study elucidates the previously unexplored relationship between PEG-CeONPs and ferroptosis in OA chondrocytes. PEG-CeONPs demonstrate anti-ferroptosis and chondroprotective effects by activating the NRF2 pathway, suggesting their potential as therapeutic agents for OA.