NFKBIZ mediates neuroprotection and maintains blood-brain barrier integrity in cerebral ischemia/reperfusion via STAT3-regulated Nrf2/ARE signaling.

Ischemic stroke (IS) is a leading cause of adult disability and mortality worldwide. It is characterized by a complex series of cellular and molecular events that lead to neuronal injury and disruption of the blood-brain barrier (BBB). The BBB plays a crucial role in maintaining brain homeostasis, and its disruption during IS exacerbates secondary brain injury. However, the molecular mechanisms that preserve BBB integrity and provide neuroprotection remain poorly understood. In this study, we used mRNA sequencing to identify genes differentially expressed in IS models. To investigate the role of NFKBIZ in BBB maintenance, we conducted additional in vitro and in vivo experiments. Mechanistic studies focused on the STAT3-mediated Nrf2/ARE signaling pathway, and metabolomic profiling was used to identify metabolites associated with NFKBIZ activity. Our findings indicate that NFKBIZ is essential for maintaining BBB integrity. Overexpression of NFKBIZ reduced ischemic injury and preserved BBB function, while its downregulation significantly worsened neurological deficits and BBB damage. The STAT3-Nrf2/ARE axis, a critical pathway for antioxidant defense, was activated by NFKBIZ, contributing to its protective effects. Furthermore, metabolomic analysis identified a set of metabolites linked to NFKBIZ function, providing insight into the underlying biological mechanisms. This study underscores the potential of NFKBIZ as a therapeutic target for neuroprotection and BBB preservation in IS, suggesting new avenues for developing treatments to improve outcomes in stroke patients.