Abstract

ABSTRACT Intervertebral disc degeneration (IVDD) is a chronic musculoskeletal disorder causing lower back pain, imposing a considerable burden on global health. Hyperglycemia resulting from diabetes mellitus induces advanced glycation end products (AGEs) accumulation in nucleus pulposus cells, leading to IVDD. Mitigating AGEs accumulation is a novel promising strategy for IVDD management. In our study, palladium nanoparticles (Pd NPs) preferentially colocalized within the endoplasmic reticulum and efficiently degraded AGEs via valosin‐containing protein (VCP)‐mediated autophagy pathways. Pd NPs promoted the ATPase activity of VCPs, upregulated microtubule‐associated proteins 1A/1B light chain 3 (LC3) expression, and increased AGEs‐degrading autophagosome production. They ameliorated mitochondrial function, relieved endoplasmic reticulum stress, and counteracted the detrimental oxidative stress microenvironment in a high‐glucose/high‐fat‐induced nucleus pulposus cell degeneration model. Consequently, Pd NPs effectively rescued nucleus pulposus cell degeneration in vitro, restored disc height and partially recovered the degenerated phenotype of IVDD in vivo. We provide novel insights regarding IVDD management by targeting AGEs degradation, showing potential for clinical practice.