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

Lipids Health Dis. 2024 Apr 29;23(1):128. doi: 10.1186/s12944-024-02116-x.


Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Ferroptosis; Lipid peroxidation; PEBP-1/15-LOX/GPX4; Sepsis-associated encephalopathy.

MeSH terms

  • Amino Acid Transport System y+ / genetics
  • Amino Acid Transport System y+ / metabolism
  • Animals
  • Child
  • Child, Preschool
  • Coenzyme A Ligases / antagonists & inhibitors
  • Coenzyme A Ligases / genetics
  • Coenzyme A Ligases / metabolism
  • Disease Models, Animal
  • Female
  • Ferroptosis* / drug effects
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus* / drug effects
  • Hippocampus* / metabolism
  • Hippocampus* / pathology
  • Humans
  • Infant
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Lipid Peroxidation* / drug effects
  • Male
  • Malondialdehyde / metabolism
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphatidylethanolamine Binding Protein* / genetics
  • Phosphatidylethanolamine Binding Protein* / metabolism
  • Phospholipid Hydroperoxide Glutathione Peroxidase* / genetics
  • Phospholipid Hydroperoxide Glutathione Peroxidase* / metabolism
  • S100 Calcium Binding Protein beta Subunit / genetics
  • S100 Calcium Binding Protein beta Subunit / metabolism
  • Sepsis / complications
  • Sepsis / drug therapy
  • Sepsis / metabolism
  • Sepsis-Associated Encephalopathy* / drug therapy
  • Sepsis-Associated Encephalopathy* / metabolism
  • Sepsis-Associated Encephalopathy* / pathology
  • Signal Transduction / drug effects


  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Phosphatidylethanolamine Binding Protein
  • Slc7a11 protein, mouse
  • Coenzyme A Ligases
  • Amino Acid Transport System y+
  • long-chain-fatty-acid-CoA ligase
  • S100 Calcium Binding Protein beta Subunit
  • Glial Fibrillary Acidic Protein
  • glutathione peroxidase 4, mouse
  • Malondialdehyde
  • Acsl4 protein, mouse