Hydrogen Sulfide Sustained Release Donor Alleviates Spinal Cord Ischemia–Reperfusion‐Induced Neuron Death by Inhibiting Ferritinophagy‐Mediated Ferroptosis

ABSTRACT Aims Spinal cord ischemia–reperfusion injury (SCIRI) is a disastrous complication that cannot be completely prevented in thoracoabdominal aneurysm surgery, leading to sensory and motor dysfunction and even paraparesis, causing tremendous socioeconomic burden. Ferritinophagy is a form of autophagic ferroptosis, which is a contributor to SCIRI. Hydrogen sulfide (H 2 S) has been reported to be neuroprotective in various diseases. However, it remains unclear whether H 2 S alleviates SCIRI‐induced neural death via regulating ferritinophagy‐mediated ferroptosis. The aim of this study was to explore their relationship and interaction in SCIRI. Results The results demonstrate that Nissl bodies and motor function were obviously lost in SCIRI rats. Meanwhile, SCIRI led to a significant increase in DHE‐positive neurons, TUNEL‐positive neurons, LC3‐positive neurons, and ferritin‐positive neurons, downregulation of GPx4, Slc7a11, p62, and ferritin expression, and upregulation of LC3 II/I and NCOA4 expression. Additionally, there was upregulation of the level of MDA, GSH, and Fe 2+ . Finally, we found that H 2 S could significantly relieve neuronal death and loss of motor function in SCIRI rats by inhibiting ferritinophagy and ferroptosis. Conclusion Ferroptosis and ferritinophagy play a crucial role in the etiopathogenesis of SCIRI, and H 2 S exerts neuroprotection by inhibiting ferritinophagy‐mediated ferroptosis.