Transl Stroke Res. 2026 Jul 17;17(4):80. doi: 10.1007/s12975-026-01474-1.
ABSTRACT
Ischemic stroke is the most prevalent form of stroke worldwide and remains a major cause of long-term disability. Impaired autophagic flux is a critical pathological mechanism that worsens neuronal injury after ischemia. This study aimed to elucidate the role of phosphatidylinositol-5-phosphate 4-kinase type II alpha (PIP4K2A) and its regulation of autophagy in cerebral ischemia/reperfusion (I/R) injury. Exploratory TMT-based serum proteomics identified PIP4K2Aas an elevated candidate protein in patients with acute ischemic stroke (AIS). Whole-blood RT-qPCR validation showed increased PIP4K2A mRNA in AIS patients and an association between higher PIP4K2A expression and lower NIHSS scores, although the small clinical cohort and peripheral sampling design preclude causal or tissue-origin conclusions. Using a transient middle cerebral artery occlusion (tMCAO) mouse model and a primary neuronal oxygen-glucose deprivation/reperfusion (OGD/R) model, we found that I/R injury markedly upregulated PIP4K2A expression in ischemic brain tissue and primary neurons. AAV-mediated PIP4K2A overexpression in vivo alleviated ischemic brain injury, preserved neuronal survival, reduced infarct volume, and improved long-term cognitive and motor functions, whereas PIP4K2A knockdown exacerbated these outcomes. In vitro, lentiviral-mediated PIP4K2A overexpression improved neuronal viability after OGD/R. Mechanistically, RNA-seq, co-immunoprecipitation, and mCherry-EGFP-LC3 tandem reporter analyses showed that PIP4K2A overexpression was associated with reduced TRIB3 mRNA and protein levels, decreased abundance of the stress-induced TRIB3-p62 complex, improved autophagic flux, and reduced autophagosomal accumulation. Concurrently, PIP4K2A-associated TRIB3 reduction was accompanied by enhanced AKT/mTOR signaling. These findings identify PIP4K2A as an endogenous protective regulator in cerebral ischemia/reperfusion injury and suggest that thePIP4K2A/TRIB3/p62 axis may represent a potential therapeutic target for ischemic stroke.
PMID:42467322 | DOI:10.1007/s12975-026-01474-1