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PIP4K2A Attenuates Cerebral Ischemia/Reperfusion Injury by Reducing the TRIB3-p62 Complex Burden and Modulating
Bodun Ma1, Xiaotian Yu1, Mei Li2
1Department of Neurology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, 215000, China.
Translational Stroke Research
|July 17, 2026
Summary
Phosphatidylinositol-5-phosphate 4-kinase type II alpha (PIP4K2A) protects against ischemic stroke by improving autophagic flux. Upregulating PIP4K2A in brain injury models reduced neuronal damage and improved function, suggesting a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Ischemic stroke is a leading cause of disability worldwide.
- Impaired autophagic flux exacerbates neuronal injury following ischemia.
- The role of specific proteins in regulating autophagy during cerebral ischemia is not fully understood.
Purpose of the Study:
- To investigate the role of phosphatidylinositol-5-phosphate 4-kinase type II alpha (PIP4K2A) in cerebral ischemia/reperfusion (I/R) injury.
- To elucidate how PIP4K2A regulates autophagy in the context of I/R injury.
Main Methods:
- Exploratory TMT-based serum proteomics and whole-blood RT-qPCR in acute ischemic stroke (AIS) patients.
- Transient middle cerebral artery occlusion (tMCAO) mouse model and oxygen-glucose deprivation/reperfusion (OGD/R) primary neuronal model.
- AAV-mediated gene manipulation (overexpression/knockdown), RNA-seq, co-immunoprecipitation, and mCherry-EGFP-LC3 tandem reporter assays.
Main Results:
- PIP4K2A was identified as an elevated protein in AIS patients and upregulated in I/R injury models.
- PIP4K2A overexpression in vivo and in vitro alleviated ischemic brain injury, preserved neurons, reduced infarct volume, and improved functional outcomes.
- PIP4K2A modulated the PIP4K2A/TRIB3/p62 axis, enhancing autophagic flux and AKT/mTOR signaling, thereby reducing neuronal damage.
Conclusions:
- PIP4K2A acts as an endogenous protective factor against cerebral I/R injury.
- The PIP4K2A/TRIB3/p62 pathway is a critical regulator of autophagy and neuronal survival in ischemic stroke.
- Targeting the PIP4K2A/TRIB3/p62 axis holds potential for novel therapeutic strategies for ischemic stroke.
