Exosomes inhibit ferroptosis to alleviate intervertebral disc degeneration via the p62-KEAP1-NRF2 pathway

Ferroptosis, an iron-dependent form of regulated cell death, has been reported to affect the activity of nucleus pulposus (NP) cells in the intervertebral disc (IVD), thereby contributing to intervertebral disc degeneration (IVDD). Exosomes (EXOs), extracellular nanovesicles that participate in intercellular communication, are potential therapeutic options for IVDD. Interestingly, while EXOs play an important role in inhibiting ferroptosis, whether EXOs from mesenchymal stem cells (MSCs) modulate the progression of IVDD through regulating ferroptosis is unclear. To reveal the role of ferroptosis in IVDD, IVD tissues with varying degrees of degeneration were collected and abnormal expression of ferroptosis markers was detected. Ferroptotic death was observed in TBHP-induced NP cell death in vitro, which can be specifically inhibited by the ferroptosis inhibitors DFO and Fer-1. Interestingly, MSC-derived EXOs alleviated TBHP-induced or RSL3-induced ferroptosis and rescued NP cell degeneration. Mechanistically, either an NRF2 inhibitor or p62 knockdown dampened the inhibitory effects of EXOs on ferroptosis, suggesting that EXOs attenuated oxidative stress-induced ferroptosis in NP cells by regulating the p62/KEAP1/NRF2 axis. Moreover, EXOs effectively alleviated IVDD in an in vivo rat model. The current study revealed that ferroptosis is associated with the development of IVDD. MSC-derived EXOs slowed IVDD progression by inhibiting NP cell ferroptosis through the p62/KEAP1/NRF2 signaling pathway, suggesting that EXOs are a potential therapeutic option for IVDD.