Abstract

Protective cerebral responses against stresses are fundamental quests of medical science. Here, we report that upregulation of histone sulfation is a protective cerebral response against ischemic injury. Ischemia upregulates the SLC26A1-PAPSS1-SULT1B1 axis, which mediates the transportation of sulfate into cells, conversion of sulfate into PAPS, and catalysis of histone sulfation (H3Y99sulf) using PAPS, respectively. Upregulated H3Y99sulf promotes metabolic genes transcription and glycolysis, sustaining cell survival in ischemic stress. In the mouse model of transient middle cerebral artery occlusion, both PAPSS1 overexpression and sulfate supplementation can boost the neuroprotective H3Y99sulf mechanism, reduce brain injury, and improve neurological functions; disruption of H3Y99sulf exacerbates ischemia-induced brain injury and counteracts the neuroprotective effect of sulfate. Ischemia patients with higher serum sulfate levels are prone to have smaller infarcts, alleviated severity assessments, and better clinical outcomes. This study unearths an undocumented protective cerebral response against ischemia that might be targeted for ischemic stroke treatment.