Clusterin Inhibits Neuronal Ferroptosis via the PI3K-AKT-mTOR-SREBP1 Axis to Promote Functional Recovery after Spinal Cord Injury

Neuronal ferroptosis is considered as a key mechanism contributing to neurological deficits during the secondary injury phase following spinal cord injury (SCI). Clusterin (CLU), a stress-responsive protein, has been reported to exert neuroprotective effects and promote neuronal survival in central nervous system injuries. However, its specific role in neuronal ferroptosis remains unclear. Here, we demonstrate that both exogenous recombinant CLU protein and endogenous CLU overexpression significantly inhibit neuronal ferroptosis, as evidenced by reduced lipid peroxidation, decreased iron accumulation, preserved mitochondrial integrity, and modulation of ferroptosis-related genes (upregulation of GPX4/xCT and downregulation of ACSL4). Mechanistically, CLU activates the PI3K-AKT-mTOR pathway, subsequently regulating the SREBP1-SCD1 lipid metabolism axis to suppress ACSL4-mediated lipid peroxidation. Furthermore, AAV-mediated CLU overexpression effectively mitigates pathological damage and significantly enhances motor function recovery in SCI mice. In conclusion, this study reveals a novel mechanism whereby CLU promotes SCI repair by inhibiting neuronal ferroptosis via the PI3K-AKT-mTOR-SREBP1 axis, indicating its therapeutic potential for ferroptosis-targeted neuroprotective strategies.