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Exosomal miR-451 Inhibits Ferroptosis by Targeting the PHD3/p53 Signaling Axis to Protect against Ischemic Stroke
Chenlu Zhu1, Jiehui Li1, Yingtao Xu1
1Graduate School, Dalian University, Dalian, Liaoning, 116622, China.
Background:
Ischemic stroke causes irreversible neuronal injury. This study investigates whether exosomal miR-451 protects against stroke by inhibiting the PHD3/p53 pathway and attenuating ferroptosis in hippocampal neurons.
Methods:
An in vitro blood-brain barrier (BBB) model was established using co-cultured mouse hippocampal neurons (HT-22), astrocytes (C8-D1A), and brain microvascular endothelial cells (bEnd.3). Cerebral ischemia-reperfusion injury was mimicked by oxygen-glucose deprivation/reoxygenation (OGD/R). Barrier integrity was validated by fluorescein sodium permeability assay, 4-h liquid level difference assay, and immunofluorescence of tight junction protein ZO-1. Engineered exosomes loaded with miR-451 were characterized by nanoparticle size analysis and electron microscopy. Following exosome treatment, ferroptosis-related markers were assessed by qRT-PCR and immunofluorescence. A PHD3 overexpression plasmid was constructed to validate the involvement of the PHD3/p53 pathway, and bioinformatics analysis identified potential downstream targets of miR-451, including YTHDF2.
Results:
miR-451-loaded exosomes increased HT-22 viability and attenuated OGD/R-induced ferroptosis. Mechanistically, miR-451 downregulated PHD3 expression, reducing p53 levels. Bioinformatics analysis revealed a negative correlation between miR-451-targeted PHD3 and YTHDF2. YTHDF2 overexpression modulated ferroptosis markers, suggesting its regulatory role in ferroptosis.
Discussion:
These findings demonstrate that miR-451 confers neuroprotection via the PHD3/p53 axis to suppress ferroptosis, with YTHDF2 serving as an additional effector. The results underscore the therapeutic promise of exosome-delivered miR-451 for ischemic stroke treatment.
Conclusion:
miR-451 protects against OGD/R-induced neuronal ferroptosis by targeting the PHD3/p53 axis, highlighting exosomal miR-451 as a potential therapeutic candidate for ischemic stroke.
Insights
Exosomal miR-451 protects hippocampal neurons from ischemic stroke by inhibiting the PHD3/p53 pathway and reducing ferroptosis. This highlights its therapeutic potential for stroke treatment.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Ischemic stroke causes irreversible neuronal damage.
- Investigating the neuroprotective role of exosomal microRNA-451 (miR-451).
- Focus on the PHD3/p53 pathway and ferroptosis in hippocampal neurons.
Purpose of the Study:
- To determine if exosomal miR-451 protects against ischemic stroke.
- To elucidate the mechanism involving the PHD3/p53 pathway and ferroptosis.
- To evaluate miR-451 as a potential therapeutic agent.
Main Methods:
- Established an in vitro blood-brain barrier model with co-cultured neurons, astrocytes, and endothelial cells.
- Mimicked ischemia-reperfusion injury using oxygen-glucose deprivation/reoxygenation (OGD/R).
- Utilized engineered exosomes loaded with miR-451, assessed ferroptosis markers, and investigated the PHD3/p53 pathway and YTHDF2 interactions.
Main Results:
- miR-451-loaded exosomes enhanced neuronal viability and reduced OGD/R-induced ferroptosis.
- miR-451 downregulated PHD3, subsequently decreasing p53 levels.
- YTHDF2 was identified as a downstream target involved in ferroptosis regulation.
Conclusions:
- Exosomal miR-451 confers neuroprotection by suppressing ferroptosis through the PHD3/p53 axis.
- YTHDF2 acts as an additional effector in this pathway.
- Exosome-delivered miR-451 shows therapeutic promise for ischemic stroke.
