CNS Neurosci Ther. 2026 Sep;32(9):e71099. doi: 10.1002/cns.71099.
ABSTRACT
BACKGROUND: Ischemic stroke (IS) is an acute cerebrovascular disease characterized by high morbidity and mortality, with limited current treatment options. Tumor protein p53-inducible nuclear protein 2 (Tp53inp2) is known to be a positive regulator of autophagy under physiological conditions, but the mechanism of Tp53inp2 in IS remains unclear. In this study, we aimed to explore the mechanism of Tp53inp2 in IS.
METHODS: Primary neural stem cells (NSCs) were extracted and identified. An OGD/R cell model was constructed. Tp53inp2 was knocked down and rapamycin was added. A middle cerebral artery occlusion (MCAO) animal model was constructed, and then 5 μL of 5 × 105 NSCs, either untreated or transfected with sh-NC or sh-Tp53inp2, were injected. Additionally, at the cellular level, Ptgs2 or Tp53inp2 was overexpressed, and METTL14 was knocked down.
RESULTS: Inhibition of Tp53inp2 mitigated OGD/R-induced mitophagy and ROS levels in vitro. Moreover, inhibition of Tp53inp2 mediated neuronal differentiation of OGD/R treated NSCs by suppressing mitophagy. At the animal level, the transplantation of NSCs with a knockdown of Tp53inp2 increased neuronal differentiation, thereby alleviating the effects of MCAO and mitigating cognitive impairments in MCAO model mice. Ptgs2 was further screened and validated as a downstream target mediating the effect of Tp53inp2 on NSCs. At the cellular level, Tp53inp2 alleviated OGD/R-induced mitophagy and ROS levels by regulating Ptgs2 expression. METTL14 could regulate Tp53inp2 expression by modulating the functional m6A modification sites on Tp53inp2 mRNA. Inhibition of METTL14 alleviated OGD/R-induced mitophagy and the rise of ROS levels in NSCs by inhibiting the Tp53inp2/Ptgs2 axis.
CONCLUSIONS: Inhibition of METTL14 alleviated OGD/R-induced neuronal differentiation injury in NSCs by inhibiting the Tp53inp2/Ptgs2 axis. By elucidating the mechanisms involving Tp53inp2, Ptgs2, and METTL14, this research offers a foundation for developing new strategies to enhance neuronal differentiation and mitigate cognitive impairments in stroke patients.
PMID:42681943 | DOI:10.1002/cns.71099