Hemorrhage-Induced Sphingosine Kinase 1 Contributes to Ferroptosis-Mediated Secondary Brain Injury in Intracerebral Hemorrhage

• Published in: Molecular neurobiology Vol. 59; no. 3; pp. 1381 - 1397
• Main Authors: Diao, Xiaojun, Cui, Qi, Tian, Ning, Zhou, Zixian, Xiang, Wenjing, Jiang, Yanlin, Deng, Jungang, Liao, Hongzhan, Lin, Xiaohui, Li, Qinghua, Liao, Rujia
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-03-2022; Springer Nature B.V
• Subjects: Apoptosis; Biomedical and Life Sciences; Biomedicine; Brain Injuries - metabolism; Brain injury; Cell Biology; Cell death; Cerebral Hemorrhage - pathology; DNA microarrays; Extracellular signal-regulated kinase; Ferroptosis; Hemorrhage; Humans; Kinases; Metabolic pathways; Neurobiology; Neurology; Neurosciences; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein kinase; siRNA; Sphingosine - metabolism; Sphingosine 1-phosphate; Sphingosine kinase; Transcription; Traumatic brain injury; Ferroptosis; Sphingosine kinase 1; Secondary brain injury; Intracerebral hemorrhage; 1-Phosphate sphingosine
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-021-02605-5

The pathogenic processes of brain injury after intracerebral hemorrhage (ICH) have not yet been fully elucidated. Increasing evidence suggests that ferroptosis activation aggravates injury after ICH, but the underlying mechanism remains unclear. Sphingosine kinase 1 (Sphk1) is a key enzyme in the regulation of sphingosine metabolism involved in the ferroptosis pathway, but its role in ICH needs clarification. In this study, transcriptional changes in ICH patients were assessed by microarray data, exposing Sphk1 as a highly upregulated gene during ICH. Furthermore, Sphk1 chemical inhibitors and siRNA were used to inhibit ICH-induced Sphk1 upregulation in in vivo and in vitro models, showing that Sphk1 inhibition after protects against ferroptosis and attenuates secondary brain injury and cell death. Mechanistically, this study unveiled that sphingosine kinase 1/sphingosine 1-phosphate/extracellular-regulated protein kinases/phosphorylated extracellular-regulated protein kinases (Sphk1/S1p/ERK/p-ERK) pathway is responsible for regulation of ferroptosis leading to secondary brain injury and cell death following ICH. Collectively, this study demonstrates that ferroptosis is closely associated with ICH, and that Sphk1 has a critical role in this lethal process. These results suggest a novel unique and effective therapeutic approach for ICH prevention and treatment.