Autophagy Suppresses Ferroptosis by Degrading TFR1 to Alleviate Cognitive Dysfunction in Mice with SAE

Du, Li-Xia; Wu, You; Jia, Qi; Li, J; Li, Yi; Hannan, MA; Fan, Zhongmin; Guo, Xingchen; Li, Ling; Peng, Yuliang; Li, Jing; Fang, Zongping; Zhang, Xijing

doi:10.1007/s10571-023-01370-4

Cited by 9 publications

(6 citation statements)

References 63 publications

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“…40 Through long-term exploration, our team found that LPS intracerebroventricular injection is stable and repeatable for behavior tests related to emotion and memory. 2,41 This finding is consistent with the results of studies conducted by various research groups on mechanisms and therapeutic targets associated with neuroinflammation. The priority of our study was to investigate the relationship between neuroinflammation of SAE and lipid metabolism in the central nervous system (CNS).…”

Section: Discussionsupporting

confidence: 89%

“…1 As a common complication of sepsis, sepsis-associated encephalopathy (SAE) is defined as a syndrome of cerebral dysfunction secondary to sepsis but in the absence of direct infection of central nervous system. 2 It has been reported that SAE occurs in approximately 70% of patients with sepsis. 3 Furthermore, clinical studies have shown that more than 60% of survivors suffer from cognitive deficits and memory impairment.…”

Section: Introductionmentioning

confidence: 99%

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Astrocytic HILPDA promotes lipid droplets generation to drive cognitive dysfunction in mice with sepsis‐associated encephalopathy

Li,

Lixia,

Gan

et al. 2024

CNS Neurosci Ther

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AimsSepsis‐associated encephalopathy (SAE) is manifested as a spectrum of disturbed cerebral function ranging from mild delirium to coma. However, the pathogenesis of SAE has not been clearly elucidated. Astrocytes play important roles in maintaining the function and metabolism of the brain. Most recently, it has been demonstrated that disorders of lipid metabolism, especially lipid droplets (LDs) dyshomeostasis, are involved in a variety of neurodegenerative diseases. The aim of this study was to investigate whether LDs are involved in the underlying mechanism of SAE.MethodsThe open field test, Y‐maze test, and contextual fear conditioning test (CFCT) were used to test cognitive function in SAE mice. Lipidomics was utilized to investigate alterations in hippocampal lipid metabolism in SAE mice. Western blotting and immunofluorescence labeling were applied for the observation of related proteins.ResultsIn the current study, we found that SAE mice showed severe cognitive dysfunction, including spatial working and contextual memory. Meanwhile, we demonstrated that lipid metabolism was widely dysregulated in the hippocampus by using lipidomic analysis. Furthermore, western blotting and immunofluorescence confirmed that LDs accumulation in hippocampal astrocytes was involved in the pathological process of cognitive dysfunction in SAE mice. We verified that LDs can be inhibited by specifically suppress hypoxia‐inducible lipid droplet‐associated protein (HILPDA) in astrocytes. Meanwhile, cognitive dysfunction in SAE was ameliorated by reducing A1 astrocyte activation and inhibiting presynaptic membrane transmitter release.ConclusionThe accumulation of astrocytic lipid droplets plays a crucial role in the pathological process of SAE. HILPDA is an attractive therapeutic target for lipid metabolism regulation and cognitive improvement in septic patients.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Astrocytic HILPDA promotes lipid droplets generation to drive cognitive dysfunction in mice with sepsis‐associated encephalopathy

Li,

Lixia,

Gan

et al. 2024

CNS Neurosci Ther

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“…124 In the study of sepsis-associated encephalopathy, it was found that the enhancement of autophagy could inhibit ferroptosis by downregulating TFR1, thereby reducing cognitive dysfunction in sepsis-associated encephalopathy mice. 125 TFR1 is responsible for the uptake of iron by cells and is a marker of ferroptosis. The accumulation of TFR1 can lead to the overload of ferrous ions in the cytoplasm, which in turn leads to the production of a large amount of ROS through the Fenton reaction, resulting in oxidative stress and even cell death.…”

Section: Egln−hif-1 Signaling Pathwaymentioning

confidence: 99%

“…Specific inhibition of HIF‐1α can observe the upregulation of macrophage autophagy and the downregulation of ferroptosis, while lipid accumulation is reduced 124 . In the study of sepsis‐associated encephalopathy, it was found that the enhancement of autophagy could inhibit ferroptosis by downregulating TFR1, thereby reducing cognitive dysfunction in sepsis‐associated encephalopathy mice 125 . TFR1 is responsible for the uptake of iron by cells and is a marker of ferroptosis.…”

Section: Potential Cross‐linking Pathways Between Autophagy and Ferro...mentioning

confidence: 99%

The association between ferroptosis and autophagy in cardiovascular diseases

Zhang,

Yang,

Ouyang

et al. 2024

Cell Biochemistry & Function

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Autophagy is a process in which cells degrade intracellular substances and play a variety of roles in cells, such as maintaining intracellular homeostasis, preventing cell overgrowth, and removing pathogens. It is highly conserved during the evolution of eukaryotic cells. So far, the study of autophagy is still a hot topic in the field of cytology. Ferroptosis is an iron‐dependent form of cell death, accompanied by the accumulation of reactive oxygen species and lipid peroxides. With the deepening of research, it has been found that ferroptosis, like autophagy, is involved in the occurrence and development of cardiovascular diseases. The relationship between autophagy and ferroptosis is complex, and the association between the two in cardiovascular disease remains to be clarified. This article reviews the mechanism of autophagy and ferroptosis and their correlation, and discusses the relationship between them in cardiovascular diseases, which is expected to provide new and important treatment strategies for cardiovascular diseases.

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“…Autophagy-dependent ferroptosis has been implicated in kidney-related diseases and cardiovascular diseases. Additionally, research by Du et al, 2023 demonstrated that rapamycin injection enhanced autophagy, leading to the downregulation of TFR1, which inhibited ferroptosis and reduced cognitive deficits in a Sepsis-associated encephalopathy (SAE) model in mice.…”

Section: Ferroptosis In Relation To Other Modes Of Cell Deathmentioning

confidence: 99%

Ferroptosis inhibitors: past, present and future

Zhang,

Luo,

Xiang

et al. 2024

Front. Pharmacol.

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Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.

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Autophagy Suppresses Ferroptosis by Degrading TFR1 to Alleviate Cognitive Dysfunction in Mice with SAE

Cited by 9 publications

References 63 publications

Astrocytic HILPDA promotes lipid droplets generation to drive cognitive dysfunction in mice with sepsis‐associated encephalopathy

Astrocytic HILPDA promotes lipid droplets generation to drive cognitive dysfunction in mice with sepsis‐associated encephalopathy

The association between ferroptosis and autophagy in cardiovascular diseases

Ferroptosis inhibitors: past, present and future

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