Research progress on the regulation of nervous system diseases by histone acetylation_West China Medical Journal

Authors：

XIAO Xuemei , LIU Xiaoyu , WANG Wendi , WANG Yongping ,  YANG Weimin

Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P. R. China;

Corresponding?author：

YANG Weimin, Email: weiminyanghn@163.com

Keywords：

Histone acetylation; epigenetic modification; cerebrovascular disease; nerve cell

DOI：

10.7507/1002-0179.202604059

Video：

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Abstract Full text Figures/Tables Video References Cited by

Epigenetic modifications include DNA methylation, RNA methylation, histone methylation, histone acetylation, and noncoding RNA. This article elucidates the molecular mechanisms by which histone modifications regulate key proteins associated with neurological disorders, focusing on how the dynamic balance between histone acetyltransferase (HAT) and histone deacetylase (HDAC) serves as an epigenetic regulatory hub, influencing disease progression through acetylation coding. It also summarizes how fluctuations in acetyl coenzyme A/nicotinamide adenine dinucleotide levels regulate cell death networks via HAT and the silence information regulator family, as well as multi-target therapeutic strategies combining HDAC inhibitors, iron chelators, and receptor-interacting protein kinase 1 inhibitors to achieve precise neuroprotection.

Citation： XIAO Xuemei, LIU Xiaoyu, WANG Wendi, WANG Yongping, YANG Weimin. Research progress on the regulation of nervous system diseases by histone acetylation. West China Medical Journal, 2026, 41(5): 710-716. doi: 10.7507/1002-0179.202604059 Copy

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3. Luger K, M?der AW, Richmond RK, et al. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature, 1997, 389(6648): 251-260.
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8. Narita T, Weinert BT, Choudhary C. Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol, 2019, 20(3): 156-174.
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15. Wu YX, Li BQ, Yu XQ, et al. Histone deacetylase 6 as a novel promising target to treat cardiovascular disease. Cancer Innov, 2024, 3(3): e114.
16. Ellmeier W, Seiser C. Histone deacetylase function in CD4⁺ T cells. Nat Rev Immunol, 2018, 18(10): 617-634.
17. Annunziato AT, Hansen JC. Role of histone acetylation in the assembly and modulation of chromatin structures. Gene Expr, 2000, 9(1/2): 37-61.
18. Nativio R, Donahue G, Berson A, et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat Neurosci, 2018, 21(4): 497-505.
19. Gr?ff J, Tsai LH. The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol, 2013, 53: 311-330.
20. Gr?ff J, Joseph NF, Horn ME, et al. Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell, 2014, 156(1/2): 261-276.
21. Settembre C, Di Malta C, Polito VA, et al. TFEB links autophagy to lysosomal biogenesis. Science, 2011, 332(6036): 1429-1433.
22. Napolitano G, Ballabio A. TFEB at a glance. J Cell Sci, 2016, 129(13): 2475-2481.
23. Settembre C, Fraldi A, Medina DL, et al. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol, 2013, 14(5): 283-296.
24. Govindarajan N, Rao P, Burkhardt S, et al. Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer’s disease. EMBO Mol Med, 2013, 5(1): 52-63.
25. Min SW, Cho SH, Zhou Y, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron, 2010, 67(6): 953-966.
26. Dixit R, Ross JL, Goldman YE, et al. Differential regulation of dynein and kinesin motor proteins by tau. Science, 2008, 319(5866): 1086-1089.
27. Fang EF, Lautrup S, Hou Y, et al. NAD⁺ in aging: molecular mechanisms and translational implications. Trends Mol Med, 2017, 23(10): 899-916.
28. Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2): 273-285.
29. Gjoneska E, Pfenning AR, Mathys H, et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature, 2015, 518(7539): 365-369.
30. Penney J, Tsai LH. Histone deacetylases in memory and cognition. Sci Signal, 2014, 7(355): re12.
31. Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol, 2019, 18(12): 1091-1102.
32. Song H, Chen J, Huang J, et al. Epigenetic modification in Parkinson’s disease. Front Cell Dev Biol, 2023, 11: 1123621.
33. Berson A, Nativio R, Berger SL, et al. Epigenetic regulation in neurodegenerative diseases. Trends Neurosci, 2018, 41(9): 587-598.
34. Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature, 1997, 388(6645): 839-840.
35. Outeiro TF, Kontopoulos E, Altmann SM, et al. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science, 2007, 317(5837): 516-519.
36. Lee JY, Koga H, Kawaguchi Y, et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J, 2010, 29(5): 969-980.
37. Anderson JP, Walker DE, Goldstein JM, et al. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem, 2006, 281(40): 29739-29752.
38. Exner N, Lutz AK, Haass C, et al. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J, 2012, 31(14): 3038-3062.
39. Wang ZL, Yuan L, Li W, et al. Ferroptosis in Parkinson’s disease: glia-neuron crosstalk. Trends Mol Med, 2022, 28(4): 258-269.
40. Qureshi IA, Mehler MF. Emerging role of epigenetics in stroke: part 1: DNA methylation and chromatin modifications. Arch Neurol, 2010, 67(11): 1316-1322.
41. Liu X, Fan B, Chopp M, et al. Epigenetic mechanisms underlying adult post stroke neurogenesis. Int J Mol Sci, 2020, 21(17): 6179.
42. Ganai SA, Ramadoss M, Mahadevan V. Histone deacetylase (HDAC) inhibitors - emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration. Curr Neuropharmacol, 2016, 14(1): 55-71.
43. Ren M, Leng Y, Jeong M, et al. Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J Neurochem, 2004, 89(6): 1358-1367.
44. Denorme F, Portier I, Rustad JL, et al. Neutrophil extracellular traps regulate ischemic stroke brain injury. J Clin Invest, 2022, 132(10): e154225.
45. Jickling GC, Liu D, Ander BP, et al. Targeting neutrophils in ischemic stroke: translational insights from experimental studies. J Cereb Blood Flow Metab, 2015, 35(6): 888-901.
46. Cuadrado E, Ortega L, Hernández-Guillamon M, et al. Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release. J Leukoc Biol, 2008, 84(1): 207-214.
47. Shakespear MR, Halili MA, Irvine KM, et al. Histone deacetylases as regulators of inflammation and immunity. Trends Immunol, 2011, 32(7): 335-343.
48. Li X, Geng X, Fan J, et al. Molecular mediators of neutrophil primary granule release following acute ischemic stroke and their associated epigenetic modulation by HDAC2. Mol Neurobiol, 2025, 62(5): 6544-6561.
49. Barnes PJ. Histone deacetylase-2 and airway disease. Ther Adv Respir Dis, 2009, 3(5): 235-243.
50. He S, Owen DR, Jelinsky SA, et al. Lysine methyltransferase SETD7 (SET7/9) regulates ROS signaling through mitochondria and NFE2L2/ARE pathway. Sci Rep, 2015, 5: 14368.
51. Du J, Zhou Y, Su X, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science, 2011, 334(6057): 806-809.
52. Nakagawa T, Lomb DJ, Haigis MC, et al. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell, 2009, 137(3): 560-570.
53. Park J, Chen Y, Tishkoff DX, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell, 2013, 50(6): 919-930.
54. Shen Z, Xiang M, Chen C, et al. Glutamate excitotoxicity: potential therapeutic target for ischemic stroke. Biomed Pharmacother, 2022, 151: 113125.
55. Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol, 2014, 115: 157-188.
56. Banoth B, Cassel SL. Mitochondria in innate immune signaling. Transl Res, 2018, 202: 52-68.
57. 黃凱, 王美堂. 血常規衍生免疫炎癥標志物與急性缺血性腦卒中相關性的研究進展. 臨床急診雜志, 2023, 24(11): 604-608.
58. Suda S, Ueda M, Nito C, et al. Valproic acid ameliorates ischemic brain injury in hyperglycemic rats with permanent middle cerebral occlusion. Brain Res, 2015, 1606: 1-8.
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West China Medical Journal

Research progress on the regulation of nervous system diseases by histone acetylation

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