Inhibition of ferroptosis protects sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a serious and common complication of sepsis. To study the ferroptosis in the pathogenesis of SAE and demonstrate the protection effect of ferroptosis resistance, cognitive function, neurological deficits, blood-brain barrier integrity and neuroinflammation were detected. SAE model was established by cecal ligation and puncture (CLP) in mice and an in vitro model was created by introducing LPS to HT22 cells. Ferroptosis inducer Fe-citrate (Fe) and ferroptosis inhibitor ferrostatin-1 (Fer-1) was post-treated in the models, respectively. SAE caused ferroptosis, as evidenced by an increase in reactive oxygen species (ROS), iron content and malondialdehyde (MDA) and a decrease in glutathione (GSH) level, as well as changes in the expression of ferroptosis-related proteins as acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), and cystine-glutamate antiporter (SLC7A11), and harmed mitochondrial function. In contrast, inhibiting ferroptosis with Fer-1 attenuated ferroptosis. Meanwhile, Fer-1 attenuated neurologic severity score, learning and memory impairment, Fluoro-Jade C (FJC) staining, and decreased Evans Blue (EB) extravasation, microglia activation and TNF-alpha and IL-1 beta production following SAE. The benefit of Fer-1 was diminished by ferroptosis inducer Fe. In addition, Fer-1 up-regulated the nuclear factor erythroid-2-related factor 2 (Nrf2)/ heme oxygenase-1(HO-1) signaling axis both in vivo and in vitro. In conclusion, our study revealed that Fer-1 might inhibit feroptosis in neurons by triggering the Nrf2/OH-1 pathway, thereby providing a therapeutic solution for SAE.