Farrerol Alleviates Hypoxic-Ischemic Encephalopathy by Inhibiting Ferroptosis in Neonatal Rats via the Nrf2 Pathway.

Farrerol (FA) is a traditional Chinese herbal medicine known for its anti-inflammatory and anti-oxidative properties in various diseases. Ferroptosis is an iron-dependent oxidative stress-induced cell death. It is characterized by lipid peroxidation and glutathione depletion and is involved in neuronal injury. However, the role of FA in inhibiting ferroptosis in hypoxic-ischemic encephalopathy (HIE) and its underlying mechanisms are not yet completely elucidated. This study aimed to investigate whether FA could mediate ferroptosis and explore its function and molecular mechanism in HIE. A neonatal rat model of HIE was used, and rats were treated with FA, ML385 (a specific inhibitor of nuclear factor erythroid 2-related factor 2 [Nrf2]), or a combination of both. Neurological deficits, infarction volume, brain water content, pathological changes, and iron ion accumulation in the brain tissues were measured using the Zea-Longa scoring system and triphenyl tetrazolium chloride (TTC), hematoxylin-eosin (HE), and Perls' staining. The expression levels of GSH-Px, MDA, SOD, and ROS in brain tissues were also evaluated. Western blot analysis was performed to analyze the expression of the Nrf2 pathway and ferroptosis-related proteins. The results showed that FA administration significantly reduced neuronal damage, infarct volume, cerebral edema, and iron ion accumulation and inhibited MDA and ROS levels while promoting GSH-Px and SOD levels. FA also increased the expression levels of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), Nrf2, and HO-1. Moreover, the combination of ML385 and FA in HIE abolished the FA protective effects. Therefore, the study concludes that FA exerts a neuroprotective effect after HIE by inhibiting oxidative stress and ferroptosis via the Nrf2 signaling pathway.