BUBR1 Facilitated Nerve Regeneration by Modulating STAT3 Phosphorylation, Thereby Alleviating HIE in Neonatal Mice

ABSTRACT Hypoxic‐ischemic encephalopathy (HIE) represents a leading cause of morbidity and mortality among neonates. However, the underlying molecular mechanisms of HIE remain largely elusive. A HIE animal model was established, and neural stem cells (NSCs) underwent oxygen‐glucose deprivation/reoxygenation (OGD/R) to mimic HIE in vitro. The HIE‐induced brain injury was evaluated using a battery of assessments, including the Morris water maze test, wire hanging test, cylinder test, TTC, TUNEL, IHC, and IF staining. Subsequently, the expressions of budding uninhibited by benzimidazoles related 1 (BUBR1) and signal transducer and activator of transcription 3 (STAT3) were examined using immunoblotting and qRT‐PCR. Furthermore, the interaction between BUBR1 and STAT3 was confirmed through co‐immunoprecipitation assays. BUBR1 was observed to be downregulated in both the HIE model and in NSCs subjected to OGD/R. Notably, the restoration of BUBR1 expression was found to alleviate the detrimental effects of HIE, primarily by facilitating nerve regeneration. Further investigation revealed that BUBR1 also mitigated OGD/R‐induced apoptosis in NSCs. Mechanistically, BUBR1 was shown to regulate the phosphorylation of STAT3, a crucial transcription factor involved in cell survival and regeneration. Moreover, BUBR1 alleviated OGD/R‐induced apoptosis of NSCs and promoted nerve regeneration to protect HIE by regulating STAT3 phosphorylation. BUBR1 facilitated nerve regeneration by modulating STAT3 phosphorylation, thereby alleviating HIE.