Identification of Cathepsin B as a Pharmacological Target for Ferroptosis after Spinal Cord Injury Via Combined Transcriptome Analysis

Spinal cord injury (SCI) is a severe traumatic disease of the central nervous system involving multiple instances of programmed cell death. Drugs targeting the pathophysiological processes in SCI remain to be developed. After SCI, hemorrhage and immune cell infiltration persist from the early to late stages. The uncleared hemosiderin causes excessive iron deposition. The ferroptosis pathways are overactivated, which causes lipid peroxidation and mitochondrial dysfunction in cells. Inhibition of ferroptosis after SCI was shown to aid functional recovery. However, the essential genes involved in the cellular ferroptosis after SCI are not known. To screen new pharmacological targets for SCI, we collected multiple transcriptomic profiles and identified differentially expressed ferroptosis driver genes. Among them, the difference in the expression of cathepsin B (CTSB) was the most significant. We also found that CTSB is abundantly expressed in macrophages after SCI and widely distributed at the epicenter of the injury. Specific inhibition of CTSB activity through a small-molecule drug, CA-074-methyl ester (CA-074-me), alleviated the disposition of metabolites and oxidative damage after SCI and promoted the recovery of the neurological function of mice.