Acute hyperglycemia impedes spinal cord injury recovery via triggering excessive ferroptosis of endothelial cells.

Spinal cord injury (SCI) is a serious central nervous system injury that often causes sensory and motor dysfunction in patients. Diabetes seriously destroys the blood spinal cord barrier (BSCB) and aggravates SCI. Ferroptosis is a new type of programmed cell death. The role of ferroptosis in diabetes-medicated BSCB destruction has not been clearly elucidated. Here, we built a type 1 diabetes (T1D) combined with SCI rat model and confirmed that hyperglycemia exacerbates SCI-mediated BSCB destruction. Pathological mechanism demonstrated that except for apoptosis, the excessive ferroptosis is another caused factor for endothelial cells (ECs) loss under hyperglycemic condition. More importantly, ferrostatin-1(a ferroptosis inhibitor) treatment significantly inhibited the ferroptosis of ECs, and promoted the BSCB repair in T1D combined with SCI rat. The mechanism study further revealed that hyperglycemia not only induces the elevated reactive oxygen species (ROS) via activating RAGE, but also suppresses the xCT expression in system Xc- in ECs, which decreases GPX4 expression and induces ferroptosis. Additionally, hyperglycemia also accelerated the transfer of iron ions from serum to spinal cord after SCI. In summary, our results suggest that the excessive ferroptosis of ECs is essential for the severe BSCB destruction in T1D combined with spinal cord injury rat.