Curcumin reduces neuroinflammation and oxidative stress in a stroke model by epigenetically regulating ADRB2 methylation through JAK2/STAT3 and Nrf2/HO-1 pathways.

The pathological mechanism of acute ischemic stroke (AIS) is complex, and exploring new diagnostic biomarkers and key molecular pathological targets is crucial for improving patient prognosis. The role of epigenetic regulation, especially DNA methylation, in AIS is receiving increasing attention, but its key target genes and clinical translational value still need to be elucidated. This study included 90 case-control groups and used pyrophosphate sequencing to detect the methylation level of β2-adrenergic receptor (ADRB2) promoter in peripheral blood. Using oxygen glucose deprivation/reperfusion (OGD/R) cell models and middle cerebral artery occlusion (MCAO) mouse models, the effects of ADRB2 expression on JAK2/STAT3 and Nrf2/HO-1 pathways, as well as inflammatory and oxidative stress factors, were evaluated using Western blot, ELISA, and other techniques. Intervention study using curcumin. The ADRB2 promoter region in the peripheral blood of AIS patients showed significant hypermethylation, and its level was significantly negatively correlated with ADRB2 mRNA and protein expression. ROC curve analysis shows that the methylation level of specific CpG sites has extremely high predictive value for AIS diagnosis (AUC ≥ 0.9). Functional experiments have confirmed that DNMT1 mediated methylation of ADRB2 increases after ischemia and hypoxia, and the downregulation of ADRB2 protein directly leads to activation of the JAK2/STAT3 pathway and inhibition of the Nrf2/HO-1 pathway, thereby synergistically exacerbating cerebral ischemic injury. Curcumin reverses the high methylation of ADRB2 by inhibiting DNMT1, upregulates ADRB2 expression, effectively improves neurological deficits, and reduces infarct volume, verifying the therapeutic feasibility of targeting this molecular pathological target. This study systematically elucidates for the first time that high methylation of ADRB2 promoter is a new biomarker and key pathological mechanism node of AIS. The first discovery of curcumin exerting neuroprotective effects through epigenetic regulation of ADRB2 expression provides a new strategy for early diagnosis and targeted therapy of AIS, as well as future targeted drugs targeting ADRB2 methylation.