Resveratrol Alleviates Intervertebral Disc Degeneration by Targeting NCOA4-Mediated Ferritinophagy Through Dual Antioxidant and Anti-Inflammatory Effects.

BACKGROUND

Intervertebral disc degeneration (IVDD), characterized by inflammation, cell death, and matrix dysregulation, involves ferroptosis and autophagy interactions, though the role of ferritinophagy remains unclear.

METHODS

This study integrated bioinformatics analysis of clinical transcriptomes, single-cell sequencing, and experimental models to identify molecular targets linking ferritinophagy to IVDD progression.

RESULTS

Multi-omics analysis revealed 10 ferroptosis-related hub genes (eg, NCOA4, TP53, SLC7A11) enriched in hypoxia, autophagy, and ferroptosis pathways. Single-cell profiling demonstrated dynamic shifts in nucleus pulposus cell (NPCs) phenotypes during degeneration, with increased pro-inflammatory monocyte/macrophage infiltration. Clinical and experimental validation showed elevated NCOA4 and ACSL4 (ferroptosis drivers) alongside reduced GPX4 and FSP1 (anti-ferroptotic factors) in degenerated discs. Mechanistically, NCOA4-mediated ferritinophagy promoted iron overload and lipid peroxidation by degrading ferritin, exacerbating oxidative damage. Resveratrol, a natural anti-inflammatory compound, mitigated IVDD in rat models by restoring disc height, suppressing IL1β, TNF-α, and IL6, and reversing ferroptosis/autophagy imbalance via NCOA4 downregulation. Cellular studies confirmed that resveratrol attenuated LPS-induced NPCs degeneration by blocking NCOA4-dependent ferritinophagy, reducing lipid peroxidation and cell death.

CONCLUSION

This work identifies NCOA4 as a critical nexus coordinating ferroptosis-autophagy crosstalk in IVDD and establishes ferritinophagy as a novel pathological mechanism. Resveratrol's therapeutic efficacy, mediated through multi-target modulation of inflammatory and iron homeostasis pathways, provides a promising strategy for IVDD treatment. The findings advance precision medicine approaches by elucidating ferritinophagy's role and proposing resveratrol as a targeted intervention to disrupt this self-amplifying cycle of oxidative damage in disc degeneration.