ZNF655-mediated neuroprotection in cerebral ischemia-reperfusion injury via Akt/Nrf2 pathway modulation.

BACKGROUND

Cerebral ischemia-reperfusion injury (CIRI) involves complex pathological processes, including oxidative stress, inflammatory responses, and apoptosis. Zinc finger protein 655 (ZNF655) is implicated in the regulation of the Akt signaling pathway, which in turn activates nuclear factor erythroid 2-related factor 2 (Nrf2) via phosphorylation, enhancing its stability and transcriptional activity. This pathway plays a critical role in mediating antioxidant defenses, suppressing inflammation, and inhibiting apoptosis. This study aimed to explore the potential neuroprotective role of ZNF655 in CIRI through modulation of the Akt/Nrf2 signaling cascade.

METHODS

An in vitro model of CIRI was established using SH-SY5Y cells subjected to oxygen-glucose deprivation followed by reoxygenation (OGD/R). Cells were infected with adenoviral vector encoding ZNF655 to upregulate ZNF655 expression. The mRNA levels were measured by real-time quantitative PCR (RT-qPCR). Protein levels were determined by immunoblotting. Cell viability was assessed via cell counting kit-8 (CCK-8) assay. Cell apoptosis was evaluated via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Oxidative stress was monitored by dichlorofluorescein diacetate (DCFH-DA) probe. Inflammatory cytokine release was detected by enzyme-linked immunosorbent assay (ELISA).

RESULTS

ZNF655 expression was significantly downregulated under OGD/R conditions compared with normoxic controls. Overexpression of ZNF655 markedly attenuated OGD/R-induced cell apoptosis, oxidative stress, and pro-inflammatory cytokine production. ZNF655 promoted Akt phosphorylation, facilitated Nrf2 nuclear translocation, and upregulated expression of downstream antioxidant genes.

CONCLUSION

Pharmacological inhibition of Akt or silencing of Nrf2 attenuated the neuroprotective effects of ZNF655. These findings indicate that ZNF655 exerts neuroprotective effects against OGD/R-induced injury by activating the Akt/Nrf2 signaling pathway.