NAC Alleviates TMJOA By Mitigating Ferroptosis In Condylar Chondrocytes

To explore the role of ferroptosis of condylar chondrocytes in temporomandibular joint osteoarthritis (TMJOA) and the therapeutic potential of N-acetylcysteine (NAC). Synovial fluid from TMJOA patients and tissue homogenates from MIA-induced TMJOA rats were collected to assess ferroptosis using assay kits for iron ions, lipid peroxides, and glutathione levels. Ferroptosis in IL1β-induced TMJOA-like condylar chondrocytes and the therapeutic effect of NAC were evaluated using assay kits, immunofluorescence staining, RT-qPCR and WB. Transcriptome and metabolome sequencing collectively elucidated the mechanistic underpinnings of NAC in regulating ferroptosis. The therapeutic effects of NAC on TMJOA rats were confirmed by Micro-CT, H&E staining, Safranin-O/Fast Green staining, and immunohistochemical staining. In TMJOA joint tissues, iron ions and lipid peroxides were elevated, while glutathione levels were reduced, and condylar chondrocytes exhibited iron overload, lipid peroxidation, abnormal glutathione metabolism, oxidative stress, and mitochondrial dysfunction. NAC demonstrated superior therapeutic efficacy compared to Ferrostatin-1, effectively rescuing ferroptosis by activating the Nrf2-Slc7A11-Gpx4 pathway, enhancing cystine transport and glutathione synthesis. In TMJOA rats, NAC showed good tissue compatibility, effectively inhibiting cartilage degradation and subchondral bone resorption, while promoting more bone tissue regeneration. This study systematically analyzes ferroptosis in TMJOA and demonstrates NAC's therapeutic potential in mitigating disease progression. NAC ameliorates IL1β-induced ferroptosis in condylar chondrocytes by activating the Nrf2-Slc7a11-Gpx4 pathway. Targeting ferroptosis may represent a promising therapeutic strategy for TMJOA, with NAC emerging as a potential therapeutic agent.