2. Academic Validation
  3. LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments

LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments

  • Cell Death Dis. 2025 Mar 1;16(1):146. doi: 10.1038/s41419-025-07469-4.
Cuiping Guo 1 2 3,  Wensheng Li 3,  Yi Liu 3,  Abdoul Razak Mahaman Yacoubou 3,  Jianzhi Wang 2 3 4,  Rong Liu 3,  Shusheng Li 5,  Xiaochuan Wang 6 7 8 9
Affiliations

Affiliations

  • 1 Department of Emergency Medicine & Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Institute of Biomedical Sciences, School of Medicine, Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, China.
  • 3 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China.
  • 5 Department of Emergency Medicine & Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Shushengli16@sina.com.
  • 6 Department of Emergency Medicine & Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wangxiaochuan@hust.edu.cn.
  • 7 Institute of Biomedical Sciences, School of Medicine, Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, China. wangxiaochuan@hust.edu.cn.
  • 8 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wangxiaochuan@hust.edu.cn.
  • 9 Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China. wangxiaochuan@hust.edu.cn.
PMID: 40025014 DOI: 10.1038/s41419-025-07469-4
Abstract

Sepsis-associated encephalopathy (SAE) is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis. Despite increasing data supporting the hypothesis of neuronal damage, the exact mechanism of sepsis-related cognitive disorders and therapeutic strategies remain unclear and need further investigation. In this study, a sepsis model was established in C57 mice using lipopolysaccharide (LPS). The findings demonstrated that LPS exposure induced neuronal loss, synaptic and cognitive deficits accompanied by mitochondrial damage. Bioinformatics and western blot analyses demonstrated a significant increase in Lipocalin-2 (LCN2) during sepsis as a key hub gene involved in immune and neurological inflammation. Interestingly, the recombinant LCN2 protein exhibited similar effects on synaptic dysfunction and cognitive deficits in C57 mice. Conversely, downregulating LCN2 effectively nullified the impact of LPS, leading to the amelioration of synaptic and cognitive deficits, neuronal loss, and Reactive Oxygen Species (ROS)-associated mitochondrial damage. These findings suggest a novel etiopathogenic mechanism of SAE, which is initiated by the increased LCN2, leading to neuronal loss and cognitive deficit. Inhibition of LCN2 could be therapeutically beneficial in treating sepsis-induced synaptic and cognitive impairments.

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