Nrf2 mitigates sepsis-associated encephalopathy-induced hippocampus ferroptosis via modulating mitochondrial dynamic...

Sepsis-associated encephalopathy (SAE) is a serious neurological complication accompanied with acute and long-term cognitive dysfunction. Ferroptosis is a newly discovered type of cell death that is produced by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis is involved in SAE. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a mitochondria related gene involved in ferroptosis. However, the role of Nrf2 in SAE and the mechanisms remains elusive. In this study, we found that Nrf2 knockout aggravated cognitive and emotional dysfunction and promoted caecal ligation and puncture (CLP)-induced brain injury and hippocampus ferroptosis as indicated by the increase of ROS, Fe²⁺ and the levels of proinflammatory cytokines. Meanwhile, the levels of glutathione peroxidase 4 (GPX4), SLC7A11 and glutathionewere downregulatedin Nrf2 knockout group. In vitro experiments showed that mitochondrial ROS, Fe²⁺ and the expression of Fis1 and Drp1 decreased, and the level of Mfn1 and Opa-1 increased after Nrf2 overexpression. The silence of Nrf2 increased the expression of ROS, MDA and Fe²⁺, while decreased glutathione, mitochondrial membrane potential (MMP) and cell viability in vitro, indicating Nrf2 improved LPS-induced mitochondrial dysfunction and mitigated hippocampal cells ferroptosis. These results suggest that Nrf2 could inhibit ferroptosis and neuroinflammation in hippocampus and reduce cognitive dysfunction in SAE mice, making it a potential therapeutic target in the treatment of SAE. The protective effects of Nrf2 on the brain may be mediated by maintaining mitochondrial dynamic homeostasis.