Reduction of lactoferrin aggravates neuronal ferroptosis after intracerebral hemorrhagic stroke in hyperglycemic mice

Diabetic hyperglycemia aggravates the prognosis of intracerebral hemorrhagic stroke (ICH) in the clinic. In addition to hematoma expansion and increased inflammation, how diabetic hyperglycemia affects the outcomes of ICH is still unclear. We found that streptozotocin-induced diabetic hyperglycemia not only increased neutrophil infiltration, but also changed the gene expression profile of neutrophils, including lactoferrin (Ltf) encoding gene Ltf. Peroxisome proliferator-activated receptor γ (PPARγ) transcribed Ltf and the lack of neutrophilic Ltf transcription and secretion exacerbated neuronal ferroptosis by accumulating intraneuronal iron. Furthermore, the administration of recombinant Ltf protected against neuronal ferroptosis and improved neurobehavior in hyperglycemic ICH mice, and vice versa. These results indicate that supplementing Ltf or inhibiting neuronal ferroptosis are promising potential strategies to improve the acute outcomes of diabetic ICH in the clinic.