Hesperetin alleviates cerebral ischemia-reperfusion injury by suppressing neuronal ferroptosis

Hesperetin (HSP), a natural flavonoid, demonstrates significant therapeutic effects on cardiovascular and cerebrovascular diseases and displays a strong application potential in the aspects of anti-inflammation and anti-oxidation. Cerebral ischemia-reperfusion is accompanied by the generation of inflammatory storms and the accumulation of reactive oxygen species (ROS), ultimately resulting in neuronal damage. While Hesperetin has been widely studied in the treatment of cardiovascular diseases, its potential for treating cerebral ischemia-reperfusion injury remains underexplored. This study aimed to discuss the potential protective mechanism of HSP on cerebral ischemia-reperfusion injury (CIRI). Ferroptosis, a form of cell death driven by iron-dependent phospholipid peroxidation is associated with neuronal damage during cerebral ischemia and subsequent reperfusion injury. Our findings indicate that HSP can confer neuronal protection after CIRI by inhibiting neuronal ferroptosis. Specifically, HSP could significantly up-regulate glutathione (GSH) levels, and up-regulate glutathione peroxidase 4(GPX4) after CIRI, thereby inhibiting cell ferroptosis. Furthermore, we observed a significant reduction in lipid peroxidation products and ROS levels, we have also obtained the same results in vivo animal experiments. In conclusion, HSP played a protective role in CIRI by regulating intracellular iron ions levels, as well as GSH and GPX4 contents to inhibit neuronal ferroptosis after CIRI.