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.