Eugenol attenuates intervertebral disc degeneration by inhibiting nucleus pulposus cell ferroptosis via the Nrf2/GPX4 pathway.

Low back pain (LBP), recognized as a prevalent musculoskeletal disorder imposing considerable socioeconomic burdens, primarily stems from intervertebral disc (IVD) degeneration. Progressive death of nucleus pulposus (NP) cells, coupled with the formation of an inflammatory setting in the NP tissue, defines this degradation. Involvement of ferroptosis, a recently discovered iron-dependent mode of programmed cell death, in the progression of intervertebral disc degeneration (IVDD) indicates potential benefits from interventions focused on ferroptosis for managing IVDD. Across numerous conditions, eugenol serves as a bioactive agent derived from nature, demonstrating antioxidant and anti-inflammatory effects; it effectively mitigates inflammatory reactions in chondrocytes that exhibit comparable avascular characteristics and morphological features to NP cells. Based on these findings, it was hypothesized that eugenol may attenuate IVDD by suppressing ferroptosis. Network pharmacology analysis combined with molecular docking demonstrated a high binding affinity between eugenol and Nrf2, a pivotal regulator in the ferroptosis pathway. These observations indicate that eugenol could influence the ferroptosis-mediated progression of IVDD, thereby offering a potential therapeutic strategy. Furthermore, in vitro studies using NP cells confirmed that eugenol upregulates both the expression and activity of the transcription factor Nrf2. In addition, shielding actions of Eugenol were observed versus ferroptosis triggered by RSL3 within NP cells. Strikingly, diminishing Nrf2 activity nullified the safeguarding role played by Eugenol in countering RSL3-provoked ferroptosis among NP cells, thereby suggesting that inhibition of ferroptosis by Eugenol occurs via activation of the Nrf2 route. Follow-up investigations performed in vivo via a rat IVDD model verified the capacity of Eugenol to hinder progression of IVDD. Taken together, such observations emphasize the promise of Eugenol as a remedy for IVDD.