FBXO2 Alleviates Intervertebral Disc Degeneration via Dual Mechanisms: Activating PINK1‐Parkin Mitophagy and Ubiquitinating LCN2 to Suppress Ferroptosis

Abstract Intervertebral disc degeneration (IVDD), a leading cause of chronic low back pain, arises from nucleus pulposus (NP) cell dysfunction due to oxidative stress‐induced mitophagy impairment and ferroptosis, though regulatory mechanisms remain unclear. F‐box only protein 2 (FBXO2), a Kruppel‐like factor 10 (KLF10)‐regulated F‐box protein, is downregulated in degenerated human NP tissues and correlates with disease severity. Overexpression of FBXO2 restores extracellular matrix (ECM) homeostasis by promoting matrix component synthesis and inhibiting catabolic enzymes, while its knockdown exacerbates ECM degradation. Under oxidative stress, FBXO2 activates PTEN‐induced putative kinase 1 (PINK1)/Parkin‐dependent mitophagy, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) accumulation. Proteomics reveals that FBXO2 suppresses ferroptosis by attenuating lipid peroxidation, glutathione depletion, and iron overload. Mechanistically, FBXO2 binds lipocalin‐2 (LCN2) via its FBA domain, promoting K27‐linked polyubiquitination to drive proteasomal degradation of this ferroptosis inducer. FBXO2 co‐expression reverses LCN2‐induced mitochondrial dysfunction and ferroptosis markers. In vivo, adeno‐associated virus 9 (AAV9)‐mediated overexpression of FBXO2 ameliorates IVDD in rats, whereas FBXO2 knockout (KO) mice exhibit exacerbated IVDD. LCN2 silencing in FBXO2‐deficient mice partially restores disc integrity and matrix component expression. These findings identify FBXO2 as a dual regulator coordinating mitophagy activation and ferroptosis suppression, offering therapeutic potential for IVDD progression.