Nodakenin attenuates intervertebral disc degeneration by regulaing ferroptosis via the Notch-c-Myc-SLC7A11 axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Nodakenin, a coumarin compound derived from Radix Angelicae Biseratae, has been traditionally recognized for its anti-inflammatory and antioxidant properties, which are relevant to the pathophysiology of intervertebral disc degeneration (IVDD) involving oxidative stress and inflammatory responses.

AIM OF THE STUDY: This study aimed to investigate the role and underlying mechanism of Nodakenin in IVDD, with a focus on its effects on ferroptosis and the Notch signaling pathway.

MATERIALS AND

METHODS

A rat model of IVDD was established to evaluate the therapeutic effects of Nodakenin. In vitro experiments were conducted to assess lipid peroxidation-dependent ferroptosis. Transcription factor target gene prediction tools and experimental validations, including promoter binding assays, were employed to examine the relationship between c-Myc and SLC7A11. The involvement of the Notch pathway was further analyzed.

RESULTS

Nodakenin significantly delayed IVDD progression in vivo and alleviated ferroptosis in vitro. Mechanistically, Nodakenin activated the Notch pathway, leading to c-Myc-mediated upregulation of SLC7A11 expression. c-Myc was confirmed to directly bind to the SLC7A11 promoter. Activation of this pathway reversed ferroptosis phenotypes and mitigated disc degeneration.

CONCLUSION

Nodakenin modulates ferroptosis through the Notch-c-Myc-SLC7A11 axis, thereby attenuating IVDD. These findings identify a potential therapeutic target for IVDD treatment and highlight the clinical relevance of Nodakenin.