Resveratrol alleviates intervertebral disc degeneration by regulating ferroptosis of nucleus pulposus cells.

Intervertebral disc degeneration (IVDD) is a major contributor to chronic low back pain, yet its molecular mechanisms remain incompletely understood. Emerging evidence suggests that ferroptosis, an iron-dependent form of regulated cell death, may play a key role in the degeneration of nucleus pulposus cells (NPCs). However, its involvement in IVDD has not been systematically explored. Resveratrol (Res), a natural polyphenol with antioxidant and cytoprotective effects, shows therapeutic potential, but its regulatory role in ferroptosis during IVDD is unclear. In this study, bulk transcriptome analysis identified 22 ferroptosis-related differentially expressed genes, among which five hub genes (GPX4, FTH1, HMOX1, NCOA4, and TFRC) were strongly linked to ferroptosis and oxidative stress pathways. Single-cell transcriptome data further revealed dynamic expression of these genes in NP cells, showing decreased GPX4 and FTH1 and increased HMOX1, NCOA4, and TFRC along the differentiation trajectory. High-dimensional weighted gene co-expression network analysis (hdWGCNA) confirmed significant associations between ferroptosis-related gene modules and IVDD pathology. Validation using human clinical samples, NP cell models, and animal experiments demonstrated that Res alleviates IVDD by modulating hub gene expression and suppressing NP cell ferroptosis. Overall, this study highlights ferroptosis as a key mechanism driving IVDD and identifies resveratrol as a promising therapeutic candidate targeting NP cell ferroptosis.