Identification of Cathepsin B as a Therapeutic Target for Ferroptosis of Macrophage after Spinal Cord Injury

Spinal cord injury (SCI) can lead to persistent neurological deficits. Excessive iron deposition and immune cell infiltration contribute to the pathological features of SCI. The study identifies Cathepsin B (CTSB) as a key gene involved in cellular ferroptosis following SCI. Inhibiting CTSB with a small-molecule drug, CA-074-methyl ester (CA-074-me), reduced lipid peroxidation and mitochondrial dysfunction in macrophages. M2-polarized macrophages are more susceptible to hemin-induced ferroptosis. CA-074-me could reduce ferroptosis, induce M2 macrophage polarization, and promote the neurological function recovery of mice after SCI. The study provides a novel molecular target for SCI treatment.

• 1
  Excessive accumulation of iron and lipid peroxide occurs in the injured epicenter after SCI, indicating ferroptosis.
• 2
  CTSB is highly expressed in myeloid cells, particularly macrophages, after SCI.
• 3
  Inhibiting CTSB with CA-074-me reduces ferroptosis in vitro by restoring mitochondrial function, reducing ROS production, and lipid peroxidation.