Related Experiment Video
Updated: Jun 22, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Neuronal ferroptosis and ferroptosis-mediated endoplasmic reticulum stress: Implications in cognitive dysfunction
PeiPei Zhong1, Lingling Li1, Xinyi Feng2
1Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuan Western Road, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, 109 Xueyuan Western Road, Wenzhou 325027, China.
Insights
Chronic intermittent hypoxia (CIH) causes cognitive dysfunction by inducing ferroptosis, a form of cell death, in the brain. Inhibiting ferroptosis and iron accumulation alleviates this dysfunction and related endoplasmic reticulum stress (ERS).
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Obstructive sleep apnea, characterized by chronic intermittent hypoxia (CIH), is associated with cognitive deficits in children.
- Ferroptosis, a cell death pathway involving iron and lipid peroxidation, is implicated in neurodegeneration but its role in CIH-induced cognitive dysfunction is unclear.
- The interplay between ferroptosis and endoplasmic reticulum stress (ERS) in the context of CIH requires further investigation.
Purpose of the Study:
- To investigate the role of ferroptosis in cognitive dysfunction induced by CIH in a mouse model.
- To explore the potential involvement of ERS in CIH-mediated ferroptosis and cognitive impairment.
- To assess the therapeutic potential of inhibiting ferroptosis and iron chelation in mitigating CIH-induced neurotoxicity.
Main Methods:
- A CIH model was established in 4-week-old male mice.
- Ferroptosis markers, ERS pathway activation (PERK-ATF4-CHOP), oxidative stress, and iron metabolism were assessed in the prefrontal cortex.
- Mice were treated with a ferroptosis inhibitor (Liproxstatin-1) and an iron chelator (Deferoxamine) to evaluate their effects.
Main Results:
- CIH induced ferroptosis in prefrontal cortex neurons, evidenced by decreased GPX4/SLC7A11 and increased lipid peroxidation, ROS, and Fe2+.
- CIH activated the ERS-related PERK-ATF4-CHOP pathway and impaired cognitive function.
- Treatment with Liproxstatin-1 and Deferoxamine ameliorated neuronal injury, cognitive deficits, reduced Fe2+, and modulated ERS markers, upregulating Nrf2.
Conclusions:
- CIH-induced cognitive impairment is mediated by neuronal ferroptosis, lipid peroxidation, iron dysregulation, and ERS in the prefrontal cortex.
- Inhibition of ferroptosis reduces ERS and cognitive dysfunction, with Nrf2 potentially playing a regulatory role.
- Targeting ferroptosis and iron metabolism presents a potential therapeutic strategy for CIH-related cognitive deficits.
Abstract:
Obstructive sleep apnea, typically characterized by chronic intermittent hypoxia (CIH), is linked to cognitive dysfunction in children. Ferroptosis, a novel form of cell death characterized by lethal iron accumulation and lipid peroxidation, is implicated in neurodegenerative diseases and ischemia-reperfusion injuries. Nevertheless, its contribution to CIH-induced cognitive dysfunction and its interaction with endoplasmic reticulum stress (ERS) remain uncertain. In this study, utilizing a CIH model in 4-week-old male mice, we investigated ferroptosis and its potential involvement in ERS regulation during cognitive dysfunction. Our findings indicate ferroptosis activation in prefrontal cortex neurons, leading to neuron loss, mitochondrial damage, decreased levels of GPX4, SLC7A11, FTL, and FTH, increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, ACSL4, TFRC, along with the activation of ERS-related PERK-ATF4-CHOP pathway. Treatment with the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) effectively mitigated the neuron injury and cognitive dysfunction induced by CIH, significantly reducing Fe2+ and partly restoring expression levels of ferroptosis-related proteins. Furhermore, the use of Lip-1 and DFO downregulated p-PERK, ATF4 and CHOP, and upregulated Nrf2 expression, suggesting that inhibiting ferroptosis reduce ERS and that the transcription factor Nrf2 is involved in the process. In summary, our findings indicate that cognitive impairment in CIH mice correlates with the induction of neuronal ferroptosis, facilitated by the System xc - GPX4 functional axis, lipid peroxidation, and the iron metabolism pathway, along with ferroptosis-mediated ERS in the prefrontal cortex. Nrf2 has been identified as a potential regulator of ferroptosis and ERS involved in the context of CIH.
