Hyperglycemia-triggered STAT3 activation drives thromboinflammation via NETs formation to promote hemorrhagic...

Hemorrhagic transformation (HT), characterized by secondary hemorrhage into the brain tissue following cerebral infarction, is a serious complication of ischemic stroke. As an independent risk factor, hyperglycemia exacerbates stroke by inducing HT, thereby increasing mortality and disability and posing an urgent clinical need. Neutrophil extracellular traps (NETs), a mediator of inflammation, are emerging as a therapeutic target after stroke. Our previous study demonstrated that NETs aggravate hyperglycemia-induced HT, however, the regulatory mechanisms of hyperglycemia in NETs formation are poorly defined. This study aimed to elucidate the mechanisms of STAT3 participating in hyperglycemia-induced HT by regulating NETs information. Network pharmacology results firstly suggested that hyperglycemic stroke-induced HT may be related to STAT3 and the regulation of NETs. Neutrophil counts, NLR (%) and NETs levels were found positively correlated with blood glucose in stroke patients. Further experiment suggested that STAT3 was activated both in high-glucose neutrophils and hyperglycemic MCAO rats. Both NETs inhibition with DNase I and STAT3 inhibition with Stattic could improve HT and BBB integrity in hyperglycemic MCAO rats, combination administration demonstrated greater efficacy. Inhibition of STAT3 alleviated thromboinflammation in hyperglycemia-induced HT rats by suppressing NETs formation and decreased levels of inflammatory factors such as IL-8 and TNF-α, and thrombosis-related factors such as vWF, TAT and Fibrinogen. This study established evidence that hyperglycemia exacerbates HT through STAT3 activation which promotes NETs formation, suggesting STAT3 as a novel target for hyperglycemia-induced HT.