New technologies for the treatment of traumatic brain injury: A narrative review of epigenetic regulation of neuroinflammation

Jiawei Xu1, #, Yanqing Zuo2, #, Tengyue Zhang3, Ye He4, Tianlin Long5, Jiao Meng1, Rui Lu6, *, Kun Xiong4, *, Yuhua Chen1, 3, 5, *

1Department of Medical Science Research Center, Brain Injury and Drug Prevention Research Key Laboratory of Shaanxi Universities, Peihua University, Xi’an, Shaanxi Province, China;

2Department of Neurosurgery, Tongling People’s Hospital, Tongling, Anhui Province, China;

3School of Life and Health Sciences, Hainan Province Key Laboratory of One Health, Collaborative Innovation Center of Life and Health, Research Team of Regulation of Cellular Senescence and Death, Hainan University, Haikou, Hainan Province, China;

4Department of Human Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China;

5Department of Neurosurgery, Bijie Traditional Chinese Medicine Hospital, Bijie, Guizhou Province, China;

6Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA

*Correspondence to: Yuhua Chen, chenyuhua.358@163.com; Kun Xiong,

xiongkun2001@163.com; Rui Lu, ruilu1@stanford.edu.

#Both authors contributed equally to this work and share first authorship.

Funding: This work was supported by the Guizhou Provincial Key Technology R&D Program, No. [2023] general 088 by Yuhua Chen), Natural Science Basic Research Program of Guizhou, No. [2024] general 586 (to TL), Natural Science Basic Research Program of Shaanxi, No. 2024SF-YBXM-217 (to YC), and No. 2024JC-YBQN-0880 (to JX), the Youth Innovation Team of Shaanxi Universities (Research on Brain Injury and Repair Research Team) and Scientific Research Project of Youth Innovation Team of Shaanxi Universities, No. 24JP137 (to YC), and the Key Laboratory of Shaanxi Universities (Brain Injury and Drug Prevention Research Laboratory) and Scientific Research Project of Key Laboratory of

Shaanxi Universities, No. 24JS038 (to JM).

Epigenetic reprogramming regulates post-traumatic brain injury inflammatory responses,

serving as both a critical regulatory mechanism and a potential biomarker for assessing

neuroinflammatory outcomes. The purpose of this review is to explore the role of epigenetics in regulating neuroinflammation following traumatic brain injury. Epigenetic mechanisms, including DNA methylation, histone modifications, RNA methylation, and non-coding RNA, influence the progression of traumatic brain injury by regulating the expression of inflammation-related genes. Accumulating evidence has shown that key inflammatory pathways play an important role in posttraumatic brain injury neuroinflammation, while epigenetic mechanisms regulate the activity of these pathways. Studies have indicated that DNA methylation influences neuroinflammation by altering

gene expression patterns; N6-methyladenosine RNA methylation dynamically regulates the stability of inflammation-related mRNAs; histone deacetylases exacerbate nerve damage by promoting the expression of inflammatory genes. Non-coding RNAs (such as miRNAs, lncRNAs, and circRNAs) further influence the progression of neuroinflammation by regulating the expression of inflammatory factors. Epigenetic therapeutic strategies, such as histone deacetylase inhibitors and non-coding RNA regulation, have shown potential therapeutic effects. However, current epigenetic therapies face challenges such as insufficient specificity, blood-brain barrier limitations, and concerns about longterm safety. Future efforts should focus on overcoming these challenges through precise delivery systems and multi-targeted therapeutic strategies. With the advancement of technology, particularly single-cell multi-omics analysis and engineered nanoparticles, epigenetic therapies hold promise as an effective approach for treating neuroinflammation following traumatic brain injury, providing new insights and a foundation for clinical precision medicine.

Key Words: epigenetic regulation; histone deacetylation; m6A; nanoparticles;

neuroinflammation; non-coding RNA; single-cell multi-omics; technology; therapeutic approaches; traumatic brain injury