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

Overview

Authors: Nashwa Amin1,2,3,4, Xia Yuan1,2, Zongjie Shi4, Fei Wu1,2, Irum Naz Abbasi1,2, Yang Yang5, Suhong Ye6, Qining Yang7, Yu Geng4, Marong Fang1,2
ORCID iDs: Marong Fang
  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
Institutions: Zhejiang Provincial People's Hospital (China); Children's Hospital (Tunisia); Hangzhou Medical College (China); Zhejiang University (China); Aswan University (Egypt); Macau University of Science and Technology (Macao SAR China); Jinhua Central Hospital (China)
Journal: ACS central science, volume 12, issue 4, pages 497-523
Dates: received 2 February 2026; accepted 6 March 2026; published online 25 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1021/acscentsci.6c00191 · PMID 42038487 · PMCID PMC13107219 · OpenAlex W7140295635
Open access: diamond, a free copy (OpenAlex)
Status: data only (how the code is found and verified)
Categories: stroke (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Topic: Neuroendocrine regulation and behavior (Endocrine and Autonomic Systems, Neuroscience), according to OpenAlex
Funding: National Natural Science Foundation of China (82272163, 82472164); Macau University of Science and Technology (FRG-25-059-FMD); Basic and Applied Basic Research Foundation of Guangdong Province (2021A1515110217); Key Research and Development Program of Zhejiang Province (2023C03003)
Citations: cited by 2 papers (Europe PMC); 62 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data Availability Statement

The authors declare that all data supporting the findings of this study are available within the article and its Supporting Information (https://pubs.acs.org/doi/suppl/10.1021/acscentsci.6c00191/suppl_file/oc6c00191_si_001.pdf) or from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 4 funders, 57 references.

Cite

This paper

Amin, N., Yuan, X., Shi, Z., Wu, F., Abbasi, I. N., Yang, Y., Ye, S., Yang, Q., Geng, Y., & Fang, M. (2026). An Epigenetic Switch for Sex-Specific Brain Resilience in Stroke: Targeting HDAC2 to Amplify Endogenous Oxytocin Signaling. ACS central science, 12(4), 497-523. https://doi.org/10.1021/acscentsci.6c00191

BibTeX

@article{amin2026epigenetic,
author = {Amin, Nashwa and Yuan, Xia and Shi, Zongjie and Wu, Fei and Abbasi, Irum Naz and Yang, Yang and Ye, Suhong and Yang, Qining and Geng, Yu and Fang, Marong},
title = {{An Epigenetic Switch for Sex-Specific Brain Resilience in Stroke: Targeting HDAC2 to Amplify Endogenous Oxytocin Signaling}},
journal = {ACS central science},
year = {2026},
month = mar,
volume = {12},
number = {4},
pages = {497--523},
publisher = {American Chemical Society},
issn = {2374-7943},
doi = {10.1021/acscentsci.6c00191},
url = {https://doi.org/10.1021/acscentsci.6c00191},
pmid = {42038487},
pmcid = {PMC13107219}
}

RIS

TY - JOUR
AU - Amin, Nashwa
AU - Yuan, Xia
AU - Shi, Zongjie
AU - Wu, Fei
AU - Abbasi, Irum Naz
AU - Yang, Yang
AU - Ye, Suhong
AU - Yang, Qining
AU - Geng, Yu
AU - Fang, Marong
TI - An Epigenetic Switch for Sex-Specific Brain Resilience in Stroke: Targeting HDAC2 to Amplify Endogenous Oxytocin Signaling
T2 - ACS central science
J2 - ACS Cent Sci
PY - 2026
DA - 2026/03/25
VL - 12
IS - 4
SP - 497
EP - 523
SN - 2374-7943
PB - American Chemical Society
DO - 10.1021/acscentsci.6c00191
UR - https://doi.org/10.1021/acscentsci.6c00191
LA - en
ER -

CSL-JSON

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