The Metastasis-associated protein 1 (MTA1) coregulator, an essential component of the nucleosome remodeling and deacetylase (NuRD) complex, potentiates neuroprotective effects against ischemia/reperfusion (I/R) injury. But the underlying mechanism(s) remain largely unknown. Here, we discovered that neuronal MTA1 was a target of oxidative stress, and stimulation of neurons with oxygen glucose deprivation (OGD) treatment significantly inhibited MTA1 expression. Additionally, MTA1 depletion augmented ischemic oxidative stress and thus promoted oxidative stress-induced neuronal cell death by OGD. While studying the impact of MTA1 status on global neuronal gene expression, we unexpectedly discovered that MTA1 may modulate OGD-induced neuronal damage via regulation of distinct nitric oxide synthase (NOS) (namely neuronal NOS, nNOS) signaling. We provided in vitro evidence that NOS1 is a chromatin target of MTA1 in OGD-insulted neurons. Mechanistically, neuronal ischemia-mediated repression of NOS1 expression is accompanied by the enhanced recruitment of MTA1 along with his tone deacetylases (HDACs) to the NOS1 promoter, which could be effectively blocked by a pharmacological inhibitor of the HDACs. These findings collectively reveal a previously unrecognized, critical homeostatic role of MTA1, both as a target and as a component of the neuronal oxidative stress, in the regulation of acute neuronal responses against brain I/R damage. Our study also provides a molecular mechanistic explanation for the previously reported neurovascular protection by selective nNOS inhibitors. (C) 2016 Elsevier Inc. All rights reserved.