Lipid peroxidation-induced ferroptosis as a therapeutic target for mitigating neuronal injury and inflammation in sepsis-associated encephalopathy: insights into the hippocampal PEBP-1/15-LOX/GPX4 pathway.

Sepsis-associated encephalopathy (SAE) refers to the widespread impairment of brain function caused by noncentral nervous system infection mediated by sepsis. Lipid peroxidation-induced ferroptosis contributes to the occurrence and course of SAE. This study aimed to investigate the relationship between neuronal injury and lipid peroxidation-induced ferroptosis in SAE. Baseline data were collected from pediatric patients upon admission, and the expression levels of various markers related to lipid peroxidation and ferroptosis were monitored in the serum and peripheral blood mononuclear cells (PBMCs) of patients with SAE as well as SAE model mice. The hippocampal phosphatidylethanolamine-binding protein (PEBP)-1/15-lysine oxidase (LOX)/ glutathione peroxidase 4 (GPX4) pathway was assessed for its role on the inhibitory effect of ferroptosis in SAE treatment. The results showed elevated levels of S100 calcium-binding protein beta (S-100β), glial fibrillary acidic protein, and malondialdehyde in the serum of SAE patients, while superoxide dismutase levels were reduced. Furthermore, analysis of PBMCs revealed increased transcription levels of PEBP1, LOX, and long-chain fatty acyl-CoA synthetase family member 4 (ACSL4) in SAE patients, while the transcription levels of GPX4 and cystine/glutamate transporter xCT (SLC7A11) were decreased. In comparison to the control group, the SAE mice exhibited increased expression of S-100β and neuron-specific enolase (NSE) in the hippocampus, whereas the expression of S-100β and NSE were reduced in deferoxamine (DFO) mice. Additionally, iron accumulation was observed in the hippocampus of SAE mice, while the iron ion levels were reduced in the DFO mice. Inhibition of ferroptosis alleviated the mitochondrial damage (as assessed by transmission electron microscopy, hippocampal mitochondrial ATP detection, and the JC-1 polymer-to-monomer ratio in the hippocampus) and the oxidative stress response induced by SAE as well as attenuated neuroinflammatory reactions. Further investigations revealed that the mechanism underlying the inhibitory effect of ferroptosis in SAE treatment is associated with the hippocampal PEBP-1/15-LOX/GPX4 pathway. These results offer potential therapeutic targets for the management of neuronal injury in SAE and valuable insights into the potential mechanisms of ferroptosis in neurological disorders.

Wang H ，Xu L ，Tang X ，Jiang Z ，Feng X ... -  《Lipids in Health and Disease》

[Hippocampal neuronal ferroptosis involved in cognitive dysfunction in rats with sepsis-related encephalopathy through the Nrf2/GPX4 signaling pathway].

Yao P ，Chen Y ，Li Y ，Zhang Y ，Qi H ，Xu W ... -  《-》

Propofol Mitigates Sepsis-Induced Brain Injury by Inhibiting Ferroptosis Via Activation of the Nrf2/HO-1axis.

Sepsis-associated encephalopathy (SAE) develops in 30-70% of hospitalized patients with sepsis. In intensive care units (ICUs), propofol is often administered to ensure an appropriate level of sedation in mechanically ventilated patients. Ferroptosis is a newly identified mode of cellular death characterized by the peroxidation of membrane lipids and excessive iron. This study was conducted to explore the interplay between propofol, sepsis, and ferroptosis. An acute systemic inflammatory model was constructed via the intraperitoneal administration of lipopolysaccharide (LPS). Nissl and Fluoro-Jade C (FJC) staining were employed to display neuronal damage and degeneration. Western blotting and immunofluorescence (IF) staining of Bax and Bcl-2 were used to confirm the neural apoptosis. QPCR of cytokines and DHE staining were used to indicate neuroinflammation. To validate ferroptosis, we assessed the content of malondialdehyde (MDA), GSH, and tissue iron, accompanied by transcription level of CHAC1, PTGS2 and GPX4. Additionally, we examined the content of acyl-CoA synthetase long-chain family member 4 (ACSL4), xCT (SLC7A11, solute carrier family 7 member 11), and glutathione peroxidase 4 (GPX4). The IF staining of Iba1-labeled microglia and GFAP-marked astrocytes were used to measure the gliosis. Erastin was pre-pretreated to confirm the anti-ferroptotic capability of propofol. ML385 was preconditioned to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in propofol-repressed ferroptosis. Propofol dose-dependently inhibited the decrease of Nissl-positive neurons and the increase of FJC-stained neurons in septic hippocampus and cortex. Neural cytokines, oxidative stress, apoptosis and gliosis were reduced by propofol. Propofol repressed the level of MDA, iron, CHAC1, PTGS2, ACLS4 and restored the content of GSH, GPX4, xCT, Nrf2 and HO-1, thus inhibiting sepsis-induced ferroptosis. All protections from propofol could be reversed by eratsin and ML385 pretreatment. Propofol protected against sepsis-induced brain damage, neuroinflammation, neuronal apoptosis and gliosis through the activation of the Nrf2/HO-1 axis to combat ferroptosis.

Zhou Y ，Yang Y ，Yi L ，Pan M ，Tang W ，Duan H ... -  《-》

Yap1 alleviates sepsis associated encephalopathy by inhibiting hippocampus ferroptosis via maintaining mitochondrial dynamic homeostasis.

Sepsis-associated encephalopathy (SAE) is a serious neurological complication accompanied by acute and long-term cognitive dysfunction. Ferroptosis is a newly discovered type of cell death that is produced by iron-dependent lipid peroxidation. As a key transcriptional coactivator in the Hippo signalling pathway, Yes-associated protein 1 (YAP1) could target ferroptosis-related genes. This study was aimed to determine whether Yap1 protects against SAE and inhibits ferroptosis via maintaining mitochondrial dynamic homeostasis. Caecal ligation puncture (CLP) was used to establish the SAE model, and LPS was applied in hippocampal cells to mimic the inflammatory model in vitro. The results showed that Yap1 conditional knockout in hippocampal caused lower survival in SAE mice and cognitive dysfunction, as proved by Morri's water maze (MWM) task, tail suspension test (TST), open field test (OFT) and elevated plus maze test (EPMT). After Yap1 knockout, the production of ROS, MDA and Fe2+ and proinflammatory cytokines in the hippocampus were increased, indicating that Yap1 deficiency exacerbates CLP-induced brain injury and hippocampus ferroptosis. Meanwhile, GPX4, SLC7A11, ferritin (FTH1) and GSH levels were decreased in the Yap1 knockout group. In vitro, Yap1 overexpression mitigated LPS-induced hippocampal cell ferroptosis and improved mitochondrial function by inhibiting mitochondrial fission, as evidenced by lower mitochondrial ROS, cell viability, Fe2+ and the expression of Fis1 and Drp1. Further, the present study suggested that Yap1 could inhibit ferritinophagy-mediated ferroptosis in the hippocampus via inhibiting mitochondrial fission, thus reducing cognitive dysfunction in SAE mice.

Yang X ，Duan H ，Li S ，Zhang J ，Dong L ，Ding J ，Li X ... -  《-》

[Changes of ferroptosis related pathways in hippocampus of mice exposed to high-altitude hypoxia].

Chang XW ，Zhao AP ，Zhong Y ，Liu FF ，Wang R ... -  《-》