Nordihydroguaiaretic acid suppresses ferroptosis and mitigates intervertebral disc degeneration through the NRF2/GPX4 axis.

Intervertebral disc degeneration (IVDD) is a major contributor to low back pain (LBP), while LBP is the leading cause of disability. However, the effective pharmacological interventions for IVDD are still lacking. Studies have elucidated that ferroptosis plays a crucial role in the pathogenesis of IVDD. This study aimed to evaluate the effects of various natural products, specifically screening for those that suppress ferroptosis induced in nucleus pulposus cells (NPCs) via RSL3. Previously, we have identified that a list of natural products in the library may suppress oxidative stress damage in NPCs, while oxidative stress is a major contributor to ferroptosis. The current study sought to verify the ferroptosis inhibitory effect of these products in NPCs. Through screening of the top 20 natural products in the list, we found that Nordihydroguaiaretic acid (NDGA) was the most effective compound to inhibit ferroptosis in NPCs. Mechanism study demonstrated that NDGA may promote the nuclear expression of the key transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently increase the expression of the ferroptosis suppressor gene GPX4, and reduce the degradation of the extracellular matrix (ECM) and suppress the progression of inflammation. In the rat puncture induced IVDD model, intraperitoneal injection of NDGA delayed the progression of IVDD. In conclusion, our study indicates that NDGA is a potential drug for the treatment of IVDD.