Oxidized low-density lipoprotein induced ferroptosis in nucleus pulposus cell contributes to intervertebral disc degeneration via LOX-1/NF-κB/NOX signal.

Oxidized low-density lipoprotein (oxLDL) activates the NF-κB signaling pathway through LOX-1, contributing to intervertebral disc degeneration (IVDD). Ferroptosis, a lipid peroxidation-driven cell death, is implicated in IVDD. This study investigates the role of ferroptosis in oxLDL-induced IVDD. Nucleus pulposus cells (NPCs) were treated with oxLDL, and ferroptosis and NF-κB p65 nuclear translocation were assessed. Bioinformatics analysis, silencing experiments, and inhibitors were used to validate the findings. In oxLDL-treated NPCs, LOX-1 and ferroptosis markers (MDA, Fe2+, lipid ROS) increased, while GSH decreased. These effects were mitigated by Liproxstatin-1 or shLOX-1. NF-κB p65 bound to LOX-1 and NOX1 promoters, forming a positive feedback loop. VAS2870 and Schisantherin A improved NPC viability and reduced ferroptosis. A mouse model showed worsening IVDD and ferroptosis over time. Clinical tissues revealed a strong correlation between LOX-1 and ferroptosis markers. oxLDL induces ferroptosis in NPCs via the LOX-1/NF-κB/NOX loop, advancing IVDD. Disrupting this loop in mice mitigated IVDD, highlighting the therapeutic potential of targeting this pathway.