LncRNA nuclear‐enriched abundant transcript 1 aggravates cerebral ischemia/reperfusion injury through activating early growth response‐1/RNA binding motif protein 25 axis

Ischemic stroke is a major global health issue. Ischemia and subsequent reperfusion results in stroke‐related brain injury. Previous studies have demonstrated that nuclear‐enriched abundant transcript 1 (NEATa and early growth response 1 (EGR1) are involved in ischemia reperfusion (IR) injury). In this study, we aimed to explore the roles of NEAT1/EGR1 axis as well as its downstream effector RNA binding motif protein 25 (RBM25) in cerebral IR injury. Oxygen–glucose deprivation/reperfusion (OGD/R) and middle cerebral artery occlusion (MCAO) were used to establish in vitro and in vivo models of cerebral IR injury, respectively. According to our data, NEAT1, EGR1, and RBM25 levels were elevated in OGD/R‐exposed SK‐N‐SH and SH‐SY5Y cells and cerebral cortex of MCAO mice. NEAT1, EGR1, or RBM25 knockdown effectively reduced infarct volumes and apoptosis, and improved neurological function. Mechanistically, NEAT1 directly interacted with EGR1, which restrained WW domain containing E3 ubiquitin protein ligase 1 (WWP1)‐mediated ubiquitination of EGR1 and subsequently caused EGR1 accumulation. EGR1 bound to RBM25 promoter and transcriptionally activated RBM25. Rescue experiments indicated that RBM25 overexpression abolished the therapeutic effects of NEAT1 knockdown. In conclusion, this work identified a novel NEAT1/EGR1/RBM25 axis in potentiating brain injury after IR insults, suggesting a potential therapeutic target for ischemic stroke. Nuclear‐enriched abundant transcript 1 (NEAT1) and early growth response 1 (EGR1) are involved in ischemia reperfusion (IR) injury. In this study, we aimed to explore the roles of NEAT1/EGR1 axis as well as its downstream effector RNA binding motif protein 25 (RBM25) in cerebral IR injury. NEAT1 could directly interact with EGR1, preventing EGR1 from WWP1‐mediated ubiquitination and subsequent degradation. NEAT1 thereby facilitated EGR1‐induced transcription and expression of RBM25, thus increasing infarct volume, neurological disorders, and cell apoptosis. We identified NEAT1‐EGR1‐RBM25 as a novel axis that was highly activated after cerebral IR injury and played an important role in the progression of cerebral IR injury. WWP1, WW domain containing E3 ubiquitin protein ligase 1.