Baicalein inhibits cerebral ischemia-reperfusion injury through SIRT6-mediated FOXA2 deacetylation to promote SLC7A11 expression

Ischemic stroke (IS) poses a serious threat to patient survival. The inhibition of ferroptosis can effectively alleviate ischemia-reperfusion (I/R) injury, suggesting potential targets in the ferroptosis pathway for the treatment of ischemic stroke. In this study, MCAO/R mice and OGD/R-induced HT22 cell were constructed. It was found that Baicalein decreased ROS, MDA, and Fe 2+ levels, upregulated GSH levels, and enhanced the expression of ferroptosis-related proteins (GPX4 and SLC7A11), downregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3), and upregulated the expression of an anti-apoptotic protein (Bcl-2), ameliorating cerebral I/R injury. In animal and cell models, SIRT6 is downregulated, and FOXA2 expression and acetylation levels are abnormally upregulated. SIRT6 inhibited FOXA2 expression and acetylation. Baicalein promoted FOXA2 deacetylation by upregulating SIRT6 expression. FOXA2 transcriptionally inhibits SLC7A11 expression. In Conclusion, Baicalein inhibited apoptosis and partially suppressed the role of ferroptosis to alleviate cerebral I/R injury via SIRT6-mediated FOXA2 deacetylation to promote SLC7A11 expression. Significance Statement Ischemic stroke (IS) is a disease of the central nervous system with high mortality and morbidity rates. Currently, effective treatments for IS are limited. Therefore, it is urgent to develop novel treatment methods. Ferroptosis inhibitors and iron chelating agents can effectively alleviate IS neuronal damage, suggesting potential targets in the ferroptosis pathway for the IS treatment. This study confirmed, for the first time, that baicalein promoted FOXA2 deacetylation by upregulating SIRT6 expression, thereby inhibiting FOXA2 transcription, leading to the upregulation of SLC7A11 expression, inhibition of apoptosis, and partial suppression of the role of ferroptosis, thus inhibiting cell apoptosis and ultimately alleviating I/R injury in IS. Our study suggests that SIRT6/FOXA2 is a target of baicalein in IS therapy.