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

Abstract

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.