2. Academic Validation
  3. An Epigenetic Switch for Sex-Specific Brain Resilience in Stroke: Targeting HDAC2 to Amplify Endogenous Oxytocin Signaling

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

  • ACS Cent Sci. 2026 Mar 25;12(4):497-523. doi: 10.1021/acscentsci.6c00191.
Nashwa Amin 1 2 3 4,  Xia Yuan 1 2,  Zongjie Shi 4,  Fei Wu 1 2,  Irum Naz Abbasi 1 2,  Yang Yang 5,  Suhong Ye 6,  Qining Yang 7,  Yu Geng 4,  Marong Fang 1 2
Affiliations

Affiliations

  • 1 Department of Orthopedics of Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Children and Adolescents' Health and Diseases, 310052 Hangzhou, China.
  • 2 Institute of System Medicine, Zhejiang University School of Medicine, Zhejiang University, 310058 Hangzhou, China.
  • 3 Department of Zoology, Faculty of Science, Aswan University, 81521 Aswan, Egypt.
  • 4 Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 310014 Hangzhou, China.
  • 5 Faculty of Medicine, Macau University of Science and Technology, Macau 999078, Taipa, China.
  • 6 Department of Neurology and Psychiatry, The Second Hospital of Jinhua, 321004 Jinhua, China.
  • 7 Department of Orthopaedics, Jinhua Municipal Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, 321000 Jinhua, China.
PMID: 42038487 DOI: 10.1021/acscentsci.6c00191
Abstract

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.

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