An Epigenetic Switch for Sex-Specific Brain Resilience in Stroke: Targeting HDAC2 to Amplify Endogenous Oxytocin Signaling

The continuous failure to account for biological sex is a key impediment to developing effective neuroprotective treatments for ischemic stroke. While epigenetic modulators such as HDAC inhibitors show promise, the mechanisms behind their sexually dimorphic effects are unknown. We present a unique, sex-specific mechanism in which HDAC2 suppression offers substantial resilience to ischemic brain injury by significantly increasing the endogenous oxytocin (OXT) signaling axis. Through integrated in vitro and in vivo models, we show that HDAC2 knockdown not only reduces infarct size and enhances functional recovery, but also does so more effectively in females. We attribute this improved protection to a strong, female-specific increase of OXT and its receptor (OTR). This increased OXT signaling, possibly mediated by estrogen, resulted in significant decreases in apoptosis, neuroinflammation, and oxidative stress. Our findings show that HDAC2 serves as a critical epigenetic brake on a built-in neuroprotective mechanism that, when activated, triggers a therapeutically potent, sex-divergent response. This study sheds light on chemical biology by identifying a druggable epigenetic target that modulates an important neurohormonal circuit. More broadly, it establishes a new paradigm for individualized stroke therapy, shifting away from a one-size-fits-all strategy and toward leveraging innate, sex-specific protective mechanisms to improve treatment efficacy.