Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, characterized by the progressive senescence of nucleus pulposus cells (NPCs) and extracellular matrix (ECM) catabolism. Although bulk autophagy has been implicated in the pathogenesis of IVDD, the specific contribution of selective autophagy to NPC fate remains largely unexplored. Here, we identify NDP52, a selective autophagy receptor, as a critical regulator of NPC homeostasis. NDP52 expression was significantly downregulated in degenerative NP tissues from humans, aged mice and needle puncture-induced IVDD models. NDP52 deficiency promoted NPC senescence, characterized by cell cycle arrest, senescence-associated secretory phenotype (SASP) factor secretion and reactive oxygen species (ROS) accumulation, ultimately leading to impaired ECM homeostasis, whereas NDP52 overexpression exerted opposite effects. In vivo, NDP52 knockout mice exhibited more severe disc degeneration and heightened pain sensitivity than wild-type controls. Deletion of the ZF2 domain abolished the protective effects of NDP52 in NPCs, indicating that its selective autophagy function is required for maintaining NPC homeostasis. Integrated proteomic and IP-MS analyses identified CAPZA1 as a candidate substrate of NDP52. Subsequent biochemical analyses demonstrated that NDP52 promotes the autophagic degradation of CAPZA1, an F-actin capping protein, through its ZF2 domain. Loss of NDP52 resulted in CAPZA1 accumulation, which was accompanied by aberrant ROS accumulation and activation of p53/Rb-dependent cell cycle arrest and NF-κB-mediated SASP signaling. CAPZA1 knockdown rescued the senescent and degenerative phenotypes caused by NDP52 deficiency. These findings identify the NDP52-CAPZA1 selective autophagy axis as a key protective mechanism against IVDD and highlight potential therapeutic targets for this prevalent degenerative disorder.
