Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Epigenetic regulation of iron metabolism and ferroptosis in Parkinson’s disease: Identifying novel epigenetic targets

Acta Pharmacologica Sinica volume 46, pages 2075–2092 (2025)Cite this article

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease, and emerging evidence has shown that iron deposition, ferroptosis and epigenetic modifications are implicated in the pathogenesis of PD. However, the interplay among these factors in PD has not been fully understood. In this review, we provide an overview of the current research progress on iron metabolism, ferroptosis and epigenetic alterations associated with PD. Furthermore, we present new frontiers concerning various epigenetic modifications related to iron metabolism and ferroptosis that might contribute to the pathology of PD. Notably, epigenetic modifications of iron metabolism and ferroptosis as both diagnostic and therapeutic targets in PD have been discussed. This opens new avenues for the regulation of iron homeostasis and ferroptosis in PD from epigenetic perspectives, and provides evidence for their potential implications in the diagnosis and treatment of PD.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Schematic diagram illustrating the process of ferroptosis.
Fig. 2: Regulatory mechanism of epigenetics modifications.
Fig. 3: Epigenetic regulation of ferroptosis in PD and the possible mechanisms involved.

Similar content being viewed by others

References

  1. Parkinson J. An essay on the shaking palsy. J Neuropsychiatry Clin Neurosci. 2002;14:223–36. https://doi.org/10.1176/jnp.14.2.223.

    Article  PubMed  Google Scholar 

  2. Dexter DT, Jenner P. Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med. 2013;62:132–44. https://doi.org/10.1016/j.freeradbiomed.2013.01.018.

    Article  CAS  PubMed  Google Scholar 

  3. Marras C, Beck JC, Bower JH, Roberts E, Ritz B, Ross GW, et al. Prevalence of Parkinson’s disease across North America. NPJ Park Dis. 2018;4:21 https://doi.org/10.1038/s41531-018-0058-0.

    Article  CAS  Google Scholar 

  4. Ben-Shlomo Y, Darweesh S, Llibre-Guerra J, Marras C, San Luciano M, Tanner C. The epidemiology of Parkinson’s disease. Lancet. 2024;403:283–92. https://doi.org/10.1016/s0140-6736(23)01419-8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Collaborators GN. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18:459–80. https://doi.org/10.1016/s1474-4422(18)30499-x.

    Article  Google Scholar 

  6. Dorsey ER, Sherer T, Okun MS, Bloem BR. The emerging evidence of the Parkinson pandemic. J Park Dis. 2018;8:S3–s8. https://doi.org/10.3233/jpd-181474.

    Article  Google Scholar 

  7. Wang J, Dai L, Chen S, Zhang Z, Fang X, Zhang Z. Protein-protein interactions regulating α-synuclein pathology. Trends Neurosci 2024;47:209–26. https://doi.org/10.1016/j.tins.2024.01.002.

    Article  CAS  PubMed  Google Scholar 

  8. Dickson DW, Fujishiro H, Orr C, DelleDonne A, Josephs KA, Frigerio R, et al. Neuropathology of non-motor features of Parkinson disease. Park Relat Disord. 2009;15:S1–5. https://doi.org/10.1016/s1353-8020(09)70769-2.

    Article  Google Scholar 

  9. Cattaneo C, Jost WH. Pain in Parkinson’s disease: pathophysiology, classification and treatment. J Integr Neurosci. 2023;22:132. https://doi.org/10.31083/j.jin2205132.

    Article  PubMed  Google Scholar 

  10. Terracciano A, Luchetti M, Karakose S, Stephan Y, Sutin AR. Loneliness and risk of Parkinson disease. JAMA Neurol. 2023;80:1138–44. https://doi.org/10.1001/jamaneurol.2023.3382.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ou R, Lin J, Liu K, Jiang Z, Wei Q, Hou Y, et al. Evolution of apathy in early Parkinson’s disease: A 4-years prospective cohort study. Front Aging Neurosci. 2020;12:620762. https://doi.org/10.3389/fnagi.2020.620762.

    Article  CAS  PubMed  Google Scholar 

  12. Broen MP, Narayen NE, Kuijf ML, Dissanayaka NN, Leentjens AF. Prevalence of anxiety in Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 2016;31:1125–33. https://doi.org/10.1002/mds.26643.

    Article  PubMed  Google Scholar 

  13. Goldman JG, Sieg E. Cognitive impairment and dementia in Parkinson disease. Clin Geriatr Med. 2020;36:365–77. https://doi.org/10.1016/j.cger.2020.01.001.

    Article  PubMed  Google Scholar 

  14. Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease: a review. JAMA. 2020;323:548–60. https://doi.org/10.1001/jama.2019.22360.

    Article  PubMed  Google Scholar 

  15. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–35. https://doi.org/10.1016/s1474-4422(06)70471-9.

    Article  PubMed  Google Scholar 

  16. Bellou V, Belbasis L, Tzoulaki I, Evangelou E, Ioannidis JP. Environmental risk factors and Parkinson’s disease: An umbrella review of meta-analyses. Park Relat Disord. 2016;23:1–9. https://doi.org/10.1016/j.parkreldis.2015.12.008.

    Article  Google Scholar 

  17. Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. The pathogenesis of Parkinson’s disease. Lancet. 2024;403:293–304. https://doi.org/10.1016/s0140-6736(23)01478-2.

    Article  CAS  PubMed  Google Scholar 

  18. Dong-Chen X, Yong C, Yang X, Chen-Yu S, Li-Hua P. Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023;8:73. https://doi.org/10.1038/s41392-023-01353-3.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Jyothi HJ, Vidyadhara DJ, Mahadevan A, Philip M, Parmar SK, Manohari SG, et al. Aging causes morphological alterations in astrocytes and microglia in human substantia nigra pars compacta. Neurobiol Aging. 2015;36:3321–33. https://doi.org/10.1016/j.neurobiolaging.2015.08.024.

    Article  CAS  PubMed  Google Scholar 

  20. Cerri S, Mus L, Blandini F. Parkinson’s disease in women and men: what’s the difference?. J Park Dis. 2019;9:501–15. https://doi.org/10.3233/jpd-191683.

    Article  Google Scholar 

  21. Zhu J, Cui Y, Zhang J, Yan R, Su D, Zhao D, et al. Temporal trends in the prevalence of Parkinson’s disease from 1980 to 2023: a systematic review and meta-analysis. Lancet Healthy Longev. 2024;5:e464–e479. https://doi.org/10.1016/s2666-7568(24)00094-1.

    Article  PubMed  Google Scholar 

  22. Marras C, Canning CG, Goldman SM. Environment, lifestyle, and Parkinson’s disease: Implications for prevention in the next decade. Mov Disord. 2019;34:801–11. https://doi.org/10.1002/mds.27720.

    Article  PubMed  Google Scholar 

  23. Chen R, Gu X, Wang X. α-Synuclein in Parkinson’s disease and advances in detection. Clin Chim Acta. 2022;529:76–86. https://doi.org/10.1016/j.cca.2022.02.006.

    Article  CAS  PubMed  Google Scholar 

  24. Siderowf A, Concha-Marambio L, Lafontant DE, Farris CM, Ma Y, Urenia PA, et al. Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023;22:407–17. https://doi.org/10.1016/s1474-4422(23)00109-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Marogianni C, Sokratous M, Dardiotis E, Hadjigeorgiou GM, Bogdanos D, Xiromerisiou G. Neurodegeneration and Inflammation-An Interesting Interplay in Parkinson’s disease. Int J Mol Sci. 2020; 21:https://doi.org/10.3390/ijms21228421.

  26. Malpartida AB, Williamson M, Narendra DP, Wade-Martins R, Ryan BJ. Mitochondrial dysfunction and mitophagy in Parkinson’s disease: from mechanism to therapy. Trends Biochem Sci. 2021;46:329–43. https://doi.org/10.1016/j.tibs.2020.11.007.

    Article  CAS  PubMed  Google Scholar 

  27. Zhao Z, Ning J, Bao XQ, Shang M, Ma J, Li G, et al. Fecal microbiota transplantation protects rotenone-induced Parkinson’s disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis. Microbiome. 2021;9:226. https://doi.org/10.1186/s40168-021-01107-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Trist BG, Hare DJ, Double KL. Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease. Aging Cell. 2019;18:e13031. https://doi.org/10.1111/acel.13031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Biondetti E, Santin MD, Valabrègue R, Mangone G, Gaurav R, Pyatigorskaya N, et al. The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson’s disease. Brain. 2021;144:3114–25. https://doi.org/10.1093/brain/awab191.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Rathore AS, Birla H, Singh SS, Zahra W, Dilnashin H, Singh R, et al. Epigenetic modulation in Parkinson’s disease and potential treatment therapies. Neurochem Res. 2021;46:1618–26. https://doi.org/10.1007/s11064-021-03334-w.

    Article  CAS  PubMed  Google Scholar 

  31. Ding XS, Gao L, Han Z, Eleuteri S, Shi W, Shen Y, et al. Ferroptosis in Parkinson’s disease: Molecular mechanisms and therapeutic potential. Ageing Res Rev. 2023;91:102077. https://doi.org/10.1016/j.arr.2023.102077.

    Article  CAS  PubMed  Google Scholar 

  32. Wang Y, Wu S, Li Q, Sun H, Wang H. Pharmacological inhibition of ferroptosis as a therapeutic target for neurodegenerative diseases and strokes. Adv Sci. 2023;10:e2300325. https://doi.org/10.1002/advs.202300325.

    Article  CAS  Google Scholar 

  33. Zhang D, Zhang J, Wang Y, Wang G, Tang P, Liu Y, et al. Targeting epigenetic modifications in Parkinson’s disease therapy. Med Res Rev. 2023;43:1748–77. https://doi.org/10.1002/med.21962.

    Article  CAS  PubMed  Google Scholar 

  34. Wei X, Cai M, Jin L. The function of the metals in regulating epigenetics during Parkinson’s disease. Front Genet. 2020;11:616083. https://doi.org/10.3389/fgene.2020.616083.

    Article  CAS  PubMed  Google Scholar 

  35. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014;13:1045–60. https://doi.org/10.1016/s1474-4422(14)70117-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Geng H, Li Z, Li Z, Zhang Y, Gao Z, Sun L, et al. Restoring neuronal iron homeostasis revitalizes neurogenesis after spinal cord injury. Proc Natl Acad Sci USA. 2023;120:e2220300120. https://doi.org/10.1073/pnas.2220300120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chifman J, Laubenbacher R, Torti SV. A systems biology approach to iron metabolism. Adv Exp Med Biol. 2014;844:201–25. https://doi.org/10.1007/978-1-4939-2095-2_10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jiang H, Wang J, Rogers J, Xie J. Brain Iron metabolism dysfunction in Parkinson’s disease. Mol Neurobiol. 2017;54:3078–101. https://doi.org/10.1007/s12035-016-9879-1.

    Article  CAS  PubMed  Google Scholar 

  39. Song N, Wang J, Jiang H, Xie J. Astroglial and microglial contributions to iron metabolism disturbance in Parkinson’s disease. Biochim Biophys Acta Mol Basis Dis. 2018;1864:967–73. https://doi.org/10.1016/j.bbadis.2018.01.008.

    Article  CAS  PubMed  Google Scholar 

  40. Zucca FA, Segura-Aguilar J, Ferrari E, Muñoz P, Paris I, Sulzer D, et al. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. 2017;155:96–119. https://doi.org/10.1016/j.pneurobio.2015.09.012.

    Article  CAS  PubMed  Google Scholar 

  41. Pyatigorskaya N, Sharman M, Corvol JC, Valabregue R, Yahia-Cherif L, Poupon F, et al. High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry. Mov Disord. 2015;30:1077–84. https://doi.org/10.1002/mds.26218.

    Article  CAS  PubMed  Google Scholar 

  42. Febbraro F, Giorgi M, Caldarola S, Loreni F, Romero-Ramos M. α-Synuclein expression is modulated at the translational level by iron. Neuroreport. 2012;23:576–80. https://doi.org/10.1097/WNR.0b013e328354a1f0.

    Article  CAS  PubMed  Google Scholar 

  43. Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B. The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci. 2000;20:6048–54. https://doi.org/10.1523/jneurosci.20-16-06048.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kaur D, Peng J, Chinta SJ, Rajagopalan S, Di Monte DA, Cherny RA, et al. Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Neurobiol Aging. 2007;28:907–13. https://doi.org/10.1016/j.neurobiolaging.2006.04.003.

    Article  CAS  PubMed  Google Scholar 

  45. Belaidi AA, Bush AI. Iron neurochemistry in Alzheimer’s disease and Parkinson’s disease: targets for therapeutics. J Neurochem. 2016;139:179–97. https://doi.org/10.1111/jnc.13425.

    Article  CAS  PubMed  Google Scholar 

  46. Guo C, Hao LJ, Yang ZH, Chai R, Zhang S, Gu Y, et al. Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice. Exp Neurol. 2016;280:13–23. https://doi.org/10.1016/j.expneurol.2016.03.016.

    Article  CAS  PubMed  Google Scholar 

  47. Ayton S, Lei P, Hare DJ, Duce JA, George JL, Adlard PA, et al. Parkinson’s disease iron deposition caused by nitric oxide-induced loss of β-amyloid precursor protein. J Neurosci. 2015;35:3591–7. https://doi.org/10.1523/jneurosci.3439-14.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Grolez G, Moreau C, Sablonnière B, Garçon G, Devedjian JC, Meguig S, et al. Ceruloplasmin activity and iron chelation treatment of patients with Parkinson’s disease. BMC Neurol. 2015;15:74. https://doi.org/10.1186/s12883-015-0331-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Devos D, Labreuche J, Rascol O, Corvol JC, Duhamel A, Guyon Delannoy P, et al. Trial of deferiprone in Parkinson’s disease. N Engl J Med. 2022;387:2045–55. https://doi.org/10.1056/NEJMoa2209254.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang N, Yu X, Song L, Xiao Z, Xie J, Xu H. Ferritin confers protection against iron-mediated neurotoxicity and ferroptosis through iron chelating mechanisms in MPP+-induced MES23.5 dopaminergic cells. Free Radic Biol Med. 2022;193:751–63. https://doi.org/10.1016/j.freeradbiomed.2022.11.018.

    Article  CAS  PubMed  Google Scholar 

  51. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. https://doi.org/10.1016/j.cell.2012.03.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bayır H, Dixon SJ, Tyurina YY, Kellum JA, Kagan VE. Ferroptotic mechanisms and therapeutic targeting of iron metabolism and lipid peroxidation in the kidney. Nat Rev Nephrol. 2023;19:315–36. https://doi.org/10.1038/s41581-023-00689-x.

    Article  CAS  PubMed  Google Scholar 

  53. Lei G, Zhuang L, Gan B. The roles of ferroptosis in cancer: Tumor suppression, tumor microenvironment, and therapeutic interventions. Cancer Cell. 2024;42:513–34. https://doi.org/10.1016/j.ccell.2024.03.011.

    Article  CAS  PubMed  Google Scholar 

  54. Sun S, Shen J, Jiang J, Wang F, Min J. Targeting ferroptosis opens new avenues for the development of novel therapeutics. Signal Transduct Target Ther. 2023;8:372. https://doi.org/10.1038/s41392-023-01606-1.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541. https://doi.org/10.1038/s41418-017-0012-4.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22:381–96. https://doi.org/10.1038/s41568-022-00459-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Li N, Jiang W, Wang W, Xiong R, Wu X, Geng Q. Ferroptosis and its emerging roles in cardiovascular diseases. Pharmacol Res. 2021;166:105466. https://doi.org/10.1016/j.phrs.2021.105466.

    Article  CAS  PubMed  Google Scholar 

  58. Ajoolabady A, Aslkhodapasandhokmabad H, Libby P, Tuomilehto J, Lip GYH, Penninger JM, et al. Ferritinophagy and ferroptosis in the management of metabolic diseases. Trends Endocrinol Metab. 2021;32:444–62. https://doi.org/10.1016/j.tem.2021.04.010.

    Article  CAS  PubMed  Google Scholar 

  59. Wang Y, Zhang M, Bi R, Su Y, Quan F, Lin Y, et al. ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury. Redox Biol. 2022;51:102262. https://doi.org/10.1016/j.redox.2022.102262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cui Y, Zhang Y, Zhao X, Shao L, Liu G, Sun C, et al. ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain Behav Immun. 2021;93:312–21. https://doi.org/10.1016/j.bbi.2021.01.003.

    Article  CAS  PubMed  Google Scholar 

  61. Bao WD, Pang P, Zhou XT, Hu F, Xiong W, Chen K, et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease. Cell Death Differ. 2021;28:1548–62. https://doi.org/10.1038/s41418-020-00685-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lin ZH, Liu Y, Xue NJ, Zheng R, Yan YQ, Wang ZX, et al. Quercetin protects against MPP(+)/MPTP-induced dopaminergic neuron death in Parkinson’s disease by inhibiting ferroptosis. Oxid Med Cell Longev. 2022;2022:7769355. https://doi.org/10.1155/2022/7769355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen X, Kang R, Kroemer G, Tang D. Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021; 218:https://doi.org/10.1084/jem.20210518.

  64. Do Van B, Gouel F, Jonneaux A, Timmerman K, Gelé P, Pétrault M, et al. Ferroptosis, a newly characterized form of cell death in Parkinson’s disease that is regulated by PKC. Neurobiol Dis. 2016;94:169–78. https://doi.org/10.1016/j.nbd.2016.05.011.

    Article  CAS  PubMed  Google Scholar 

  65. Guiney SJ, Adlard PA, Bush AI, Finkelstein DI, Ayton S. Ferroptosis and cell death mechanisms in Parkinson’s disease. Neurochem Int. 2017;104:34–48. https://doi.org/10.1016/j.neuint.2017.01.004.

    Article  CAS  PubMed  Google Scholar 

  66. Agostini F, Bubacco L, Chakrabarti S, Bisaglia M. α-Synuclein toxicity in drosophila melanogaster is enhanced by the presence of iron: implications for Parkinson’s disease. Antioxidants. 2023; 12:https://doi.org/10.3390/antiox12020261.

  67. Bjørklund G, Peana M, Maes M, Dadar M, Severin B. The glutathione system in Parkinson’s disease and its progression. Neurosci Biobehav Rev. 2021;120:470–8. https://doi.org/10.1016/j.neubiorev.2020.10.004.

    Article  CAS  PubMed  Google Scholar 

  68. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, et al. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol. 1994;36:348–55. https://doi.org/10.1002/ana.410360305.

    Article  CAS  PubMed  Google Scholar 

  69. Zeng X, An H, Yu F, Wang K, Zheng L, Zhou W, et al. Benefits of iron chelators in the treatment of Parkinson’s disease. Neurochem Res. 2021;46:1239–51. https://doi.org/10.1007/s11064-021-03262-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Faucheux BA, Martin ME, Beaumont C, Hunot S, Hauw JJ, Agid Y, et al. Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson’s disease. J Neurochem. 2002;83:320–30. https://doi.org/10.1046/j.1471-4159.2002.01118.x.

    Article  CAS  PubMed  Google Scholar 

  71. Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59:298–308. https://doi.org/10.1016/j.molcel.2015.06.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575:688–92. https://doi.org/10.1038/s41586-019-1705-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–98. https://doi.org/10.1038/nchembio.2239.

    Article  CAS  PubMed  Google Scholar 

  74. Yuan H, Li X, Zhang X, Kang R, Tang D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478:1338–43. https://doi.org/10.1016/j.bbrc.2016.08.124.

    Article  CAS  PubMed  Google Scholar 

  75. Yue M, Wei J, Chen W, Hong D, Chen T, Fang X. Neurotrophic role of the next-generation probiotic Strain L. lactis MG1363-pMG36e-GLP-1 on Parkinson’s disease via inhibiting ferroptosis. Nutrients. 2022; 14:https://doi.org/10.3390/nu14224886.

  76. Song LM, Xiao ZX, Zhang N, Yu XQ, Cui W, Xie JX, et al. Apoferritin improves motor deficits in MPTP-treated mice by regulating brain iron metabolism and ferroptosis. iScience. 2021;24:102431. https://doi.org/10.1016/j.isci.2021.102431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hu ZW, Wen YH, Ma RQ, Chen L, Zeng XL, Wen WP, et al. Ferroptosis Driver SOCS1 and Suppressor FTH1 independently correlate with M1 and M2 macrophage infiltration in head and neck squamous cell carcinoma. Front Cell Dev Biol. 2021;9:727762. https://doi.org/10.3389/fcell.2021.727762.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Tian Y, Lu J, Hao X, Li H, Zhang G, Liu X, et al. FTH1 inhibits ferroptosis through ferritinophagy in the 6-OHDA model of Parkinson’s disease. Neurotherapeutics. 2020;17:1796–812. https://doi.org/10.1007/s13311-020-00929-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dai CQ, Luo TT, Luo SC, Wang JQ, Wang SM, Bai YH, et al. p53 and mitochondrial dysfunction: novel insight of neurodegenerative diseases. J Bioenerg Biomembr. 2016;48:337–47. https://doi.org/10.1007/s10863-016-9669-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Goiran T, Duplan E, Rouland L, El Manaa W, Lauritzen I, Dunys J, et al. Nuclear p53-mediated repression of autophagy involves PINK1 transcriptional down-regulation. Cell Death Differ. 2018;25:873–84. https://doi.org/10.1038/s41418-017-0016-0.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Amit M, Takahashi H, Dragomir MP, Lindemann A, Gleber-Netto FO, Pickering CR, et al. Loss of p53 drives neuron reprogramming in head and neck cancer. Nature. 2020;578:449–54. https://doi.org/10.1038/s41586-020-1996-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mogi M, Kondo T, Mizuno Y, Nagatsu T. p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the Parkinsonian brain. Neurosci Lett. 2007;414:94–7. https://doi.org/10.1016/j.neulet.2006.12.003.

    Article  CAS  PubMed  Google Scholar 

  83. Kamath T, Abdulraouf A, Burris SJ, Langlieb J, Gazestani V, Nadaf NM, et al. Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease. Nat Neurosci. 2022;25:588–95. https://doi.org/10.1038/s41593-022-01061-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ishii T, Bannai S, Sugita Y. Mechanism of growth stimulation of L1210 cells by 2-mercaptoethanol in vitro. Role of the mixed disulfide of 2-mercaptoethanol and cysteine. J Biol Chem. 1981;256:12387–92.

    Article  CAS  PubMed  Google Scholar 

  85. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62. https://doi.org/10.1038/nature14344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Riegel G, Orvain C, Recberlik S, Spaety ME, Poschet G, Venkatasamy A, et al. The unfolded protein response-glutathione metabolism axis: a novel target of a cycloruthenated complexes bypassing tumor resistance mechanisms. Cancer Lett. 2024;585:216671. https://doi.org/10.1016/j.canlet.2024.216671.

    Article  CAS  PubMed  Google Scholar 

  87. Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 2015;10:1604–9. https://doi.org/10.1021/acschembio.5b00245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Skonieczna M, Cieslar-Pobuda A, Saenko Y, Foksinski M, Olinski R, Rzeszowska-Wolny J, et al. The Impact of DIDS-Induced Inhibition of Voltage-Dependent Anion Channels (VDAC) on cellular response of lymphoblastoid cells to ionizing radiation. Med Chem. 2017;13:477–83. https://doi.org/10.2174/1573406413666170421102353.

    Article  CAS  PubMed  Google Scholar 

  89. Kuhn H, Banthiya S, van Leyen K. Mammalian lipoxygenases and their biological relevance. Biochim Biophys Acta. 2015;1851:308–30. https://doi.org/10.1016/j.bbalip.2014.10.002.

    Article  CAS  PubMed  Google Scholar 

  90. Lin F, Chen W, Zhou J, Zhu J, Yao Q, Feng B, et al. Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury. Cell Death Dis. 2022;13:271. https://doi.org/10.1038/s41419-022-04708-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Razavi SM, Khayatan D, Arab ZN, Momtaz S, Zare K, Jafari RM, et al. Licofelone, a potent COX/5-LOX inhibitor and a novel option for treatment of neurological disorders. Prostagl Other Lipid Mediat. 2021;157:106587. https://doi.org/10.1016/j.prostaglandins.2021.106587.

    Article  CAS  Google Scholar 

  92. Ryan SK, Zelic M, Han Y, Teeple E, Chen L, Sadeghi M, et al. Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration. Nat Neurosci. 2023;26:12–26. https://doi.org/10.1038/s41593-022-01221-3.

    Article  CAS  PubMed  Google Scholar 

  93. Lu H, Zhang B, Yin T, Hua Y, Cao C, Ge M, et al. Ferroptosis-related immune genes in hematological diagnosis of Parkinson’s diseases. Mol Neurobiol. 2023;60:6395–409. https://doi.org/10.1007/s12035-023-03468-8.

    Article  CAS  PubMed  Google Scholar 

  94. Li K, Wang M, Huang Z-H, Wang M, Sun W-Y, Kurihara H, et al. ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis. Pharmacol Res. 2023;193:106779. https://doi.org/10.1016/j.phrs.2023.106779.

    Article  CAS  PubMed  Google Scholar 

  95. Shi L, Huang C, Luo Q, Xia Y, Liu W, Zeng W, et al. Clioquinol improves motor and non-motor deficits in MPTP-induced monkey model of Parkinson’s disease through AKT/mTOR pathway. Aging. 2020;12:9515–33. https://doi.org/10.18632/aging.103225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sun Y, He L, Wang W, Xie Z, Zhang X, Wang P, et al. Activation of Atg7-dependent autophagy by a novel inhibitor of the Keap1-Nrf2 protein-protein interaction from Penthorum Chinense Pursh. attenuates 6-hydroxydopamine-induced ferroptosis in zebrafish and dopaminergic neurons. Food Funct. 2022;13:7885–7900. https://doi.org/10.1039/d2fo00357k.

    Article  CAS  PubMed  Google Scholar 

  97. Xi J, Zhang Z, Wang Z, Wu Q, He Y, Xu Y, et al. Hinokitiol functions as a ferroptosis inhibitor to confer neuroprotection. Free Radic Biol Med. 2022;190:202–15. https://doi.org/10.1016/j.freeradbiomed.2022.08.011.

    Article  CAS  PubMed  Google Scholar 

  98. Wang L, An H, Yu F, Yang J, Ding H, Bao Y, et al. The neuroprotective effects of paeoniflorin against MPP+-induced damage to dopaminergic neurons via the Akt/Nrf2/GPX4 pathway. J Chem Neuroanat. 2022;122:102103. https://doi.org/10.1016/j.jchemneu.2022.102103.

    Article  CAS  PubMed  Google Scholar 

  99. Sun Y, He L, Wang T, Hua W, Qin H, Wang J, et al. Activation of p62-Keap1-Nrf2 Pathway Protects 6-Hydroxydopamine-Induced ferroptosis in dopaminergic cells. Mol Neurobiol. 2020;57:4628–41. https://doi.org/10.1007/s12035-020-02049-3.

    Article  CAS  PubMed  Google Scholar 

  100. Liu L, Yang S, Wang H. α-Lipoic acid alleviates ferroptosis in the MPP+-induced PC12 cells via activating the PI3K/Akt/Nrf2 pathway. Cell Biol Int. 2021;45:422–31. https://doi.org/10.1002/cbin.11505.

    Article  CAS  PubMed  Google Scholar 

  101. Marupudi N, Xiong MP. Genetic targets and applications of iron chelators for neurodegeneration with brain iron accumulation. ACS Bio Med Chem Au. 2024;4:119–30. https://doi.org/10.1021/acsbiomedchemau.3c00066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Negida A, Hassan NM, Aboeldahab H, Zain YE, Negida Y, Cadri S, et al. Efficacy of the iron-chelating agent, deferiprone, in patients with Parkinson’s disease: A systematic review and meta-analysis. CNS Neurosci Ther. 2024;30:e14607. https://doi.org/10.1111/cns.14607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128:635–8. https://doi.org/10.1016/j.cell.2007.02.006.

    Article  CAS  PubMed  Google Scholar 

  104. Zhang L, Lu Q, Chang C. Epigenetics in health and disease. Adv Exp Med Biol. 2020;1253:3–55. https://doi.org/10.1007/978-81-15-3449-2_1.

    Article  CAS  PubMed  Google Scholar 

  105. Recillas-Targa F. Cancer epigenetics: an overview. Arch Med Res. 2022;53:732–40. https://doi.org/10.1016/j.arcmed.2022.11.003.

    Article  CAS  PubMed  Google Scholar 

  106. Wang G, Wang B, Yang P. Epigenetics in congenital heart disease. J Am Heart Assoc. 2022;11:e025163. https://doi.org/10.1161/jaha.121.025163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Prasher D, Greenway SC, Singh RB. The impact of epigenetics on cardiovascular disease. Biochem Cell Biol. 2020;98:12–22. https://doi.org/10.1139/bcb-2019-0045.

    Article  CAS  PubMed  Google Scholar 

  108. Ling C, Rönn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab. 2019;29:1028–44. https://doi.org/10.1016/j.cmet.2019.03.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gao X, Chen Q, Yao H, Tan J, Liu Z, Zhou Y, et al. Epigenetics in Alzheimer’s disease. Front Aging Neurosci. 2022;14:911635. https://doi.org/10.3389/fnagi.2022.911635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sharma R, Bisht P, Kesharwani A, Murti K, Kumar N. Epigenetic modifications in Parkinson’s disease: A critical review. Eur J Pharmacol. 2024;975:176641. https://doi.org/10.1016/j.ejphar.2024.176641.

    Article  CAS  PubMed  Google Scholar 

  111. Burgunder JM. Mechanisms underlying phenotypic variation in neurogenetic disorders. Nat Rev Neurol. 2023;19:363–70. https://doi.org/10.1038/s41582-023-00811-4.

    Article  CAS  PubMed  Google Scholar 

  112. Berson A, Nativio R, Berger SL, Bonini NM. Epigenetic regulation in neurodegenerative diseases. Trends Neurosci. 2018;41:587–98. https://doi.org/10.1016/j.tins.2018.05.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Li J, Jaiswal MK, Chien JF, Kozlenkov A, Jung J, Zhou P, et al. Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation. Nat Commun. 2023;14:5714. https://doi.org/10.1038/s41467-023-41033-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hotchkiss RD. The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J Biol Chem. 1948;175:315–32.

    Article  CAS  PubMed  Google Scholar 

  115. Sigurpalsdottir BD, Stefansson OA, Holley G, Beyter D, Zink F, Hardarson M, et al. A comparison of methods for detecting DNA methylation from long-read sequencing of human genomes. Genome Biol. 2024;25:69. https://doi.org/10.1186/s13059-024-03207-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Simmons RK, Stringfellow SA, Glover ME, Wagle AA, Clinton SM. DNA methylation markers in the postnatal developing rat brain. Brain Res. 2013;1533:26–36. https://doi.org/10.1016/j.brainres.2013.08.005.

    Article  CAS  PubMed  Google Scholar 

  117. He Y, Zheng Z, Liu C, Li W, Zhao L, Nie G, et al. Inhibiting DNA methylation alleviates cisplatin-induced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway. Acta Pharm Sin B. 2022;12:1305–21. https://doi.org/10.1016/j.apsb.2021.11.002.

    Article  CAS  PubMed  Google Scholar 

  118. Suelves M, Carrió E, Núñez-Álvarez Y, Peinado MA. DNA methylation dynamics in cellular commitment and differentiation. Brief Funct Genomics. 2016;15:443–53. https://doi.org/10.1093/bfgp/elw017.

    Article  CAS  PubMed  Google Scholar 

  119. Jowaed A, Schmitt I, Kaut O, Wüllner U. Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. J Neurosci. 2010;30:6355–9. https://doi.org/10.1523/jneurosci.6119-09.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schmitt I, Evert BO, Sharma A, Khazneh H, Murgatroyd C, Wüllner U. The Alpha-Synuclein Gene (SNCA) is a genomic target of methyl-CpG Binding Protein 2 (MeCP2)-implications for Parkinson’s disease and Rett syndrome. Mol Neurobiol. 2024. https://doi.org/10.1007/s12035-024-03974-3.

  121. Bogdanović O, Smits AH, de la Calle Mustienes E, Tena JJ, Ford E, Williams R, et al. Active DNA demethylation at enhancers during the vertebrate phylotypic period. Nat Genet. 2016;48:417–26. https://doi.org/10.1038/ng.3522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhang X, Zhang Y, Wang C, Wang X. TET (Ten-eleven translocation) family proteins: structure, biological functions and applications. Signal Transduct Target Ther. 2023;8:297. https://doi.org/10.1038/s41392-023-01537-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Guhathakurta S, Song MK, Basu S, Je G, Cristovao AC, Kim YS. Regulation of αlpha-synuclein gene (SNCA) by epigenetic modifier TET1 in Parkinson disease. Int Neurourol J. 2022;26:S85–93. https://doi.org/10.5213/inj.2222206.103.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Kaas GA, Zhong C, Eason DE, Ross DL, Vachhani RV, Ming GL, et al. TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron. 2013;79:1086–93. https://doi.org/10.1016/j.neuron.2013.08.032.

    Article  CAS  PubMed  Google Scholar 

  125. Li Y, Qu C, Song H, Li T, Zheng J, Wu L, et al. Enriched environment priors to TET1 hippocampal administration for regulating psychiatric behaviors via glial reactivity in chronic cerebral hypoperfusion models. J Affect Disord. 2022;310:198–212. https://doi.org/10.1016/j.jad.2022.04.087.

    Article  CAS  PubMed  Google Scholar 

  126. Shu L, Qin L, Min S, Pan H, Zhong J, Guo J, et al. Genetic analysis of DNA methylation and hydroxymethylation genes in Parkinson’s disease. Neurobiol Aging. 2019;84:242.e13–242.e16. https://doi.org/10.1016/j.neurobiolaging.2019.02.025.

    Article  CAS  PubMed  Google Scholar 

  127. Kaut O, Schmitt I, Tost J, Busato F, Liu Y, Hofmann P, et al. Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson’s disease revealed different epigenetic patterns in peripheral blood mononuclear cells. Neurogenetics. 2017;18:7–22. https://doi.org/10.1007/s10048-016-0497-x.

    Article  CAS  PubMed  Google Scholar 

  128. Bate C, Williams A. cAMP-inhibits cytoplasmic phospholipase A2 and protects neurons against Amyloid-β-induced synapse damage. Biology. 2015;4:591–606. https://doi.org/10.3390/biology4030591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gurevich VV, Gurevich EV. A boost in learning by removing nuclear phosphodiesterases and enhancing nuclear cAMP signaling. Sci Signal. 2023;16:eadg9504. https://doi.org/10.1126/scisignal.adg9504.

    Article  PubMed  Google Scholar 

  130. Morató X, Garcia-Esparcia P, Argerich J, Llorens F, Zerr I, Paslawski W, et al. Ecto-GPR37: a potential biomarker for Parkinson’s disease. Transl Neurodegener. 2021;10:8. https://doi.org/10.1186/s40035-021-00232-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet. 2009;41:1308–12. https://doi.org/10.1038/ng.487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Reed LA, Wszolek ZK, Hutton M. Phenotypic correlations in FTDP-17. Neurobiol Aging. 2001;22:89–107. https://doi.org/10.1016/s0197-4580(00)00202-5.

    Article  CAS  PubMed  Google Scholar 

  133. Soutar MPM, Melandri D, O’Callaghan B, Annuario E, Monaghan AE, Welsh NJ, et al. Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at 16q11.2 and MAPT H1 loci. Brain. 2022;145:4349–67. https://doi.org/10.1093/brain/awac325.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Su X, Chu Y, Kordower JH, Li B, Cao H, Huang L, et al. PGC-1α promoter methylation in Parkinson’s disease. PLoS One. 2015;10:e0134087. https://doi.org/10.1371/journal.pone.0134087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Henderson AR, Wang Q, Meechoovet B, Siniard AL, Naymik M, De Both M, et al. DNA methylation and expression profiles of whole blood in Parkinson’s disease. Front Genet. 2021;12:640266. https://doi.org/10.3389/fgene.2021.640266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kochmanski J, Kuhn NC, Bernstein AI. Parkinson’s disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons. NPJ Park Dis. 2022;8:120. https://doi.org/10.1038/s41531-022-00355-2.

    Article  CAS  Google Scholar 

  137. Lin Q, Ding H, Zheng Z, Gu Z, Ma J, Chen L, et al. Promoter methylation analysis of seven clock genes in Parkinson’s disease. Neurosci Lett. 2012;507:147–50. https://doi.org/10.1016/j.neulet.2011.12.007.

    Article  CAS  PubMed  Google Scholar 

  138. Kaut O, Schmitt I, Wüllner U. Genome-scale methylation analysis of Parkinson’s disease patients’ brains reveals DNA hypomethylation and increased mRNA expression of cytochrome P450 2E1. Neurogenetics. 2012;13:87–91. https://doi.org/10.1007/s10048-011-0308-3

    Article  CAS  PubMed  Google Scholar 

  139. Searles Nielsen S, Checkoway H, Criswell SR, Farin FM, Stapleton PL, Sheppard L, et al. Inducible nitric oxide synthase gene methylation and parkinsonism in manganese-exposed welders. Parkinsonism Relat Disord. 2015;21:355–60. https://doi.org/10.1016/j.parkreldis.2015.01.007.

    Article  PubMed  Google Scholar 

  140. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature. 1997;389:251–60. https://doi.org/10.1038/38444.

    Article  CAS  PubMed  Google Scholar 

  141. Weake VM, Workman JL. Histone ubiquitination: triggering gene activity. Mol Cell. 2008;29:653–63. https://doi.org/10.1016/j.molcel.2008.02.014.

    Article  CAS  PubMed  Google Scholar 

  142. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95. https://doi.org/10.1038/cr.2011.22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Gopalan S, Wang Y, Harper NW, Garber M, Fazzio TG. Simultaneous profiling of multiple chromatin proteins in the same cells. Mol Cell. 2021;81:4736–.e5. https://doi.org/10.1016/j.molcel.2021.09.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Bartosovic M, Castelo-Branco G. Multimodal chromatin profiling using nanobody-based single-cell CUT&Tag. Nat Biotechnol. 2023;41:794–805. https://doi.org/10.1038/s41587-022-01535-4.

    Article  CAS  PubMed  Google Scholar 

  145. Meers MP, Llagas G, Janssens DH, Codomo CA, Henikoff S. Multifactorial profiling of epigenetic landscapes at single-cell resolution using MulTI-Tag. Nat Biotechnol. 2023;41:708–16. https://doi.org/10.1038/s41587-022-01522-9.

    Article  CAS  PubMed  Google Scholar 

  146. Stuart T, Hao S, Zhang B, Mekerishvili L, Landau DA, Maniatis S, et al. Nanobody-tethered transposition enables multifactorial chromatin profiling at single-cell resolution. Nat Biotechnol. 2023;41:806–12. https://doi.org/10.1038/s41587-022-01588-5.

    Article  CAS  PubMed  Google Scholar 

  147. Xiong H, Wang Q, Li CC, He A. Single-cell joint profiling of multiple epigenetic proteins and gene transcription. Sci Adv. 2024;10:eadi3664. https://doi.org/10.1126/sciadv.adi3664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Yue X, Xie Z, Li M, Wang K, Li X, Zhang X, et al. Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing. Nat Commun. 2022;13:7939. https://doi.org/10.1038/s41467-022-35650-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10:295–304. https://doi.org/10.1038/nrg2540.

    Article  CAS  PubMed  Google Scholar 

  150. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128:693–705. https://doi.org/10.1016/j.cell.2007.02.005.

    Article  CAS  PubMed  Google Scholar 

  151. Evans LW, Stratton MS, Ferguson BS. Dietary natural products as epigenetic modifiers in aging-associated inflammation and disease. Nat Prod Rep. 2020;37:653–76. https://doi.org/10.1039/c9np00057g.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wu Y, Ma J, Yang X, Nan F, Zhang T, Ji S, et al. Neutrophil profiling illuminates anti-tumor antigen-presenting potency. Cell. 2024;187:1422–.e24. https://doi.org/10.1016/j.cell.2024.02.005.

    Article  CAS  PubMed  Google Scholar 

  153. Zhang S, Zhang Y, Duan X, Wang B, Zhan Z. Targeting NPM1 epigenetically promotes postinfarction cardiac repair by reprogramming reparative macrophage metabolism. Circulation. 2024;149:1982–2001. https://doi.org/10.1161/circulationaha.123.065506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Wu YL, Lin ZJ, Li CC, Lin X, Shan SK, Guo B, et al. Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study. Signal Transduct Target Ther. 2023;8:98. https://doi.org/10.1038/s41392-023-01333-7.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Sanacora G, Yan Z, Popoli M. The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders. Nat Rev Neurosci. 2022;23:86–103. https://doi.org/10.1038/s41583-021-00540-x.

    Article  CAS  PubMed  Google Scholar 

  156. Mazzocchi M, Goulding SR, Morales-Prieto N, Foley T, Collins LM, Sullivan AM, et al. Peripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson’s disease. Brain Behav Immun. 2022;102:151–60. https://doi.org/10.1016/j.bbi.2022.02.025.

    Article  CAS  PubMed  Google Scholar 

  157. Pradeepa MM, Grimes GR, Kumar Y, Olley G, Taylor GC, Schneider R, et al. Histone H3 globular domain acetylation identifies a new class of enhancers. Nat Genet. 2016;48:681–6. https://doi.org/10.1038/ng.3550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Pandey R, Müller A, Napoli CA, Selinger DA, Pikaard CS, Richards EJ, Bender J, Mount DW, Jorgensen RA, et al. Analysis of histone acetyltransferase and histone deacetylase families of Arabidopsis thaliana suggests functional diversification of chromatin modification among multicellular eukaryotes. Nucleic Acids Res. 2002;30:5036–55. https://doi.org/10.1093/nar/gkf660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kumar V, Kundu S, Singh A, Singh S. Understanding the role of histone deacetylase and their inhibitors in neurodegenerative disorders: current targets and future perspective. Curr Neuropharmacol. 2022;20:158–78. https://doi.org/10.2174/1570159x19666210609160017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Sardoiwala MN, Sood A, Biswal L, Roy Choudhury S, Karmakar S. Reconstituted super paramagnetic protein “magnetotransferrin” for brain targeting to attenuate Parkinsonism. ACS Appl Mater Interfaces. 2023;15:12708–18. https://doi.org/10.1021/acsami.2c20990.

    Article  CAS  PubMed  Google Scholar 

  161. Marinho D, Ferreira IL, Lorenzoni R, Cardoso SM, Santana I, Rego AC. Reduction of class I histone deacetylases ameliorates ER-mitochondria cross-talk in Alzheimer’s disease. Aging Cell. 2023;22:e13895. https://doi.org/10.1111/acel.13895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Lang C, Campbell KR, Ryan BJ, Carling P, Attar M, Vowles J, et al. Single-cell sequencing of iPSC-dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes. Cell Stem Cell. 2019;24:93–106.e6. https://doi.org/10.1016/j.stem.2018.10.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Dai X, Lin A, Zhuang L, Zeng Q, Cai L, Wei Y, et al. Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2024;49:942–52. https://doi.org/10.1038/s41386-023-01775-1.

    Article  CAS  PubMed  Google Scholar 

  164. Mondal P, Bai P, Gomm A, Bakiasi G, Lin CJ, Wang Y, et al. Structure-based discovery of a small molecule inhibitor of histone deacetylase 6 (HDAC6) that significantly reduces Alzheimer’s disease neuropathology. Adv Sci. 2024;11:e2304545. https://doi.org/10.1002/advs.202304545.

    Article  CAS  Google Scholar 

  165. Lee SH, Lee JH, Lee HY, Min KJ. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019;52:24–34. https://doi.org/10.5483/BMBRep.2019.52.1.290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Wang Y, Lv D, Liu W, Li S, Chen J, Shen Y, et al. Disruption of the circadian clock alters antioxidative defense via the SIRT1-BMAL1 Pathway in 6-OHDA-induced models of Parkinson’s disease. Oxid Med Cell Longev. 2018;2018:4854732. https://doi.org/10.1155/2018/4854732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Singh P, Hanson PS, Morris CM. SIRT1 ameliorates oxidative stress induced neural cell death and is down-regulated in Parkinson’s disease. BMC Neurosci. 2017;18:46. https://doi.org/10.1186/s12868-017-0364-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Li X, Feng Y, Wang XX, Truong D, Wu YC. The critical role of SIRT1 in Parkinson’s disease: mechanism and therapeutic considerations. Aging Dis. 2020;11:1608–22. https://doi.org/10.14336/ad.2020.0216.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Arbo BD, André-Miral C, Nasre-Nasser RG, Schimith LE, Santos MG, Costa-Silva D, et al. Resveratrol derivatives as potential treatments for Alzheimer’s and Parkinson’s disease. Front Aging Neurosci. 2020;12:103. https://doi.org/10.3389/fnagi.2020.00103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Sun F, Wang J, Meng L, Zhou Z, Xu Y, Yang M, et al. AdipoRon promotes amyloid-β clearance through enhancing autophagy via nuclear GAPDH-induced sirtuin 1 activation in Alzheimer’s disease. Br J Pharmacol. 2024;181:3039–63. https://doi.org/10.1111/bph.16400.

    Article  CAS  PubMed  Google Scholar 

  171. Thapa R, Moglad E, Afzal M, Gupta G, Bhat AA, Hassan Almalki W, et al. The role of sirtuin 1 in ageing and neurodegenerative disease: A molecular perspective. Ageing Res Rev. 2024;102:102545. https://doi.org/10.1016/j.arr.2024.102545.

    Article  CAS  PubMed  Google Scholar 

  172. Gebremedhin KG, Rademacher DJ. Histone H3 acetylation in the postmortem Parkinson’s disease primary motor cortex. Neurosci Lett. 2016;627:121–5. https://doi.org/10.1016/j.neulet.2016.05.060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Toker L, Tran GT, Sundaresan J, Tysnes OB, Alves G, Haugarvoll K, et al. Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain. Mol Neurodegener. 2021;16:31. https://doi.org/10.1186/s13024-021-00450-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Huang M, Lou D, Charli A, Kong D, Jin H, Zenitsky G, et al. Mitochondrial dysfunction-induced H3K27 hyperacetylation perturbs enhancers in Parkinson’s disease. JCI Insight. 2021; 6:https://doi.org/10.1172/jci.insight.138088.

  175. Gardian G, Yang L, Cleren C, Calingasan NY, Klivenyi P, Beal MF. Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity. Neuromolecular Med. 2004;5:235–41. https://doi.org/10.1385/nmm:5:3:235.

    Article  CAS  PubMed  Google Scholar 

  176. Zhou W, Bercury K, Cummiskey J, Luong N, Lebin J, Freed CR. Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem. 2011;286:14941–51. https://doi.org/10.1074/jbc.M110.211029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kulkarni A, Preeti K, Tryphena KP, Srivastava S, Singh SB, Khatri DK. Proteostasis in Parkinson’s disease: Recent development and possible implication in diagnosis and therapeutics. Ageing Res Rev. 2023;84:101816. https://doi.org/10.1016/j.arr.2022.101816.

    Article  CAS  PubMed  Google Scholar 

  178. Meka ST, Bojja SL, Kumar G, Birangal SR, Rao CM. Novel HDAC inhibitors provide neuroprotection in MPTP-induced Parkinson’s disease model of rats. Eur J Pharmacol. 2023;959:176067. https://doi.org/10.1016/j.ejphar.2023.176067.

    Article  CAS  PubMed  Google Scholar 

  179. Toledano-Pinedo M, Porro-Pérez A, Schäker-Hübner L, Romero F, Dong M, Samadi A, et al. Contilisant+Tubastatin A Hybrids: polyfunctionalized indole derivatives as new HDAC inhibitor-based multitarget small molecules with in vitro and in vivo activity in neurodegenerative diseases. J Med Chem. 2024;67:16533–55. https://doi.org/10.1021/acs.jmedchem.4c01367.

    Article  CAS  PubMed  Google Scholar 

  180. Fnu S, Williamson EA, De Haro LP, Brenneman M, Wray J, Shaheen M, et al. Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining. Proc Natl Acad Sci USA. 2011;108:540–5. https://doi.org/10.1073/pnas.1013571108.

    Article  PubMed  Google Scholar 

  181. Sugeno N, Jäckel S, Voigt A, Wassouf Z, Schulze-Hentrich J, Kahle PJ. α-Synuclein enhances histone H3 lysine-9 dimethylation and H3K9me2-dependent transcriptional responses. Sci Rep. 2016;6:36328. https://doi.org/10.1038/srep36328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Guhathakurta S, Kim J, Adams L, Basu S, Song MK, Adler E, et al. Targeted attenuation of elevated histone marks at SNCA alleviates α-synuclein in Parkinson’s disease. EMBO Mol Med. 2021;13:e12188. https://doi.org/10.15252/emmm.202012188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Mu MD, Qian ZM, Yang SX, Rong KL, Yung WH, Ke Y. Therapeutic effect of a histone demethylase inhibitor in Parkinson’s disease. Cell Death Dis. 2020;11:927. https://doi.org/10.1038/s41419-020-03105-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–79. https://doi.org/10.1146/annurev.biochem.67.1.425.

    Article  CAS  PubMed  Google Scholar 

  185. Srivastava AK, Choudhury SR, Karmakar S. Neuronal Bmi-1 is critical for melatonin induced ubiquitination and proteasomal degradation of α-synuclein in experimental Parkinson’s disease models. Neuropharmacology. 2021;194:108372. https://doi.org/10.1016/j.neuropharm.2020.108372.

    Article  CAS  PubMed  Google Scholar 

  186. Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV, Murchison E, et al. A MicroRNA feedback circuit in midbrain dopamine neurons. Science. 2007;317:1220–4. https://doi.org/10.1126/science.1140481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Chen Q, Deng N, Lu K, Liao Q, Long X, Gou D, et al. Elevated plasma miR-133b and miR-221-3p as biomarkers for early Parkinson’s disease. Sci Rep. 2021;11:15268. https://doi.org/10.1038/s41598-021-94734-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Doxakis E. Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153. J Biol Chem. 2010;285:12726–34. https://doi.org/10.1074/jbc.M109.086827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Thome AD, Harms AS, Volpicelli-Daley LA, Standaert DG. microRNA-155 regulates alpha-synuclein-induced inflammatory responses in models of Parkinson disease. J Neurosci. 2016;36:2383–90. https://doi.org/10.1523/jneurosci.3900-15.2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. McMillan KJ, Murray TK, Bengoa-Vergniory N, Cordero-Llana O, Cooper J, Buckley A, et al. Loss of microRNA-7 regulation leads to α-synuclein accumulation and dopaminergic neuronal loss in vivo. Mol Ther. 2017;25:2404–14. https://doi.org/10.1016/j.ymthe.2017.08.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Kabaria S, Choi DC, Chaudhuri AD, Mouradian MM, Junn E. Inhibition of miR-34b and miR-34c enhances α-synuclein expression in Parkinson’s disease. FEBS Lett. 2015;589:319–25. https://doi.org/10.1016/j.febslet.2014.12.014.

    Article  CAS  PubMed  Google Scholar 

  192. Citterio LA, Mancuso R, Agostini S, Meloni M, Clerici M. Serum and exosomal miR-7-1-5p and miR-223-3p as possible biomarkers for Parkinson’s disease. Biomolecules. 2023; 13:https://doi.org/10.3390/biom13050865.

  193. Vallelunga A, Ragusa M, Di Mauro S, Iannitti T, Pilleri M, Biundo R, et al. Identification of circulating microRNAs for the differential diagnosis of Parkinson’s disease and Multiple System Atrophy. Front Cell Neurosci. 2014;8:156. https://doi.org/10.3389/fncel.2014.00156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Chen Y, Gao C, Sun Q, Pan H, Huang P, Ding J, et al. MicroRNA-4639 Is a regulator of DJ-1 expression and a potential early diagnostic marker for Parkinson’s disease. Front Aging Neurosci. 2017;9:232. https://doi.org/10.3389/fnagi.2017.00232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. He L, Chen Y, Lin S, Shen R, Pan H, Zhou Y, et al. Regulation of Hsa-miR-4639-5p expression and its potential role in the pathogenesis of Parkinson’s disease. Aging Cell. 2023;22:e13840. https://doi.org/10.1111/acel.13840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Goh SY, Chao YX, Dheen ST, Tan EK, Tay SS. Role of MicroRNAs in Parkinson’s disease. Int J Mol Sci. 2019;20:5649. https://doi.org/10.3390/ijms20225649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Schulz J, Takousis P, Wohlers I, Itua IOG, Dobricic V, Rücker G, et al. Meta-analyses identify differentially expressed microRNAs in Parkinson’s disease. Ann Neurol. 2019;85:835–51. https://doi.org/10.1002/ana.25490.

    Article  CAS  PubMed  Google Scholar 

  198. Yang Z, Li T, Cui Y, Li S, Cheng C, Shen B, et al. Elevated Plasma microRNA-105-5p level in patients with idiopathic Parkinson’s disease: a potential disease biomarker. Front Neurosci. 2019;13:218. https://doi.org/10.3389/fnins.2019.00218.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Schließer P, Struebing FL, Northoff BH, Kurz A, Rémi J, Holdt L, et al. Detection of a Parkinson’s disease-specific MicroRNA signature in nasal and oral swabs. Mov Disord. 2023;38:1706–15. https://doi.org/10.1002/mds.29515.

    Article  CAS  PubMed  Google Scholar 

  200. Li T, Tan X, Tian L, Jia C, Cheng C, Chen X, et al. The role of Nurr1-miR-30e-5p-NLRP3 axis in inflammation-mediated neurodegeneration: insights from mouse models and patients’ studies in Parkinson’s disease. J Neuroinflammation. 2023;20:274. https://doi.org/10.1186/s12974-023-02956-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Pollini L, Galosi S, Nardecchia F, Musacchia F, Castello R, Nigro V, et al. Parkinsonism, intellectual disability, and catatonia in a young male with MECP2 variant. Mov Disord Clin Pract. 2020;7:118–9. https://doi.org/10.1002/mdc3.12865.

    Article  PubMed  Google Scholar 

  202. Cao Q, Zou Q, Zhao X, Zhang Y, Qu Y, Wang N, et al. Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity. Cell Death Discov. 2022;8:267. https://doi.org/10.1038/s41420-022-01063-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: From synaptic regulation to psychiatric disorders. Cell. 2022;185:62–76. https://doi.org/10.1016/j.cell.2021.12.003.

    Article  CAS  PubMed  Google Scholar 

  204. Brauer R, Wei L, Ma T, Athauda D, Girges C, Vijiaratnam N, et al. Diabetes medications and risk of Parkinson’s disease: a cohort study of patients with diabetes. Brain. 2020;143:3067–76. https://doi.org/10.1093/brain/awaa262.

    Article  PubMed  PubMed Central  Google Scholar 

  205. Jan TY, Wong LC, Yang MT, Huang CJ, Hsu CJ, Peng SS, et al. Correlation of dystonia severity and iron accumulation in Rett syndrome. Sci Rep. 2021;11:838. https://doi.org/10.1038/s41598-020-80723-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Zhang X, Huang Z, Xie Z, Chen Y, Zheng Z, Wei X, et al. Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4. Free Radic Biol Med. 2020;160:552–65. https://doi.org/10.1016/j.freeradbiomed.2020.08.029.

    Article  CAS  PubMed  Google Scholar 

  207. Periñán MT, Macías-García D, Jesús S, Martín-Rodríguez JF, Muñoz-Delgado L, Jimenez-Jaraba MV, et al. Homocysteine levels, genetic background, and cognitive impairment in Parkinson’s disease. J Neurol. 2023;270:477–85. https://doi.org/10.1007/s00415-022-11361-y.

    Article  CAS  PubMed  Google Scholar 

  208. Bai L, Yan F, Deng R, Gu R, Zhang X, Bai J. Thioredoxin-1 rescues MPP+/MPTP-Induced ferroptosis by increasing glutathione peroxidase 4. Mol Neurobiol. 2021;58:3187–97. https://doi.org/10.1007/s12035-021-02320-1.

    Article  CAS  PubMed  Google Scholar 

  209. Huang Z, Han J, Wu P, Wu C, Fan Y, Zhao L, et al. Sorting nexin 5 plays an important role in promoting ferroptosis in Parkinson’s Disease. Oxid Med Cell Longev. 2022;2022:5463134. https://doi.org/10.1155/2022/5463134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Shi Q, Liu R, Chen L. Ferroptosis inhibitor ferrostatin‑1 alleviates homocysteine‑induced ovarian granulosa cell injury by regulating TET activity and DNA methylation. Mol Med Rep. 2022;25:130. https://doi.org/10.3892/mmr.2022.12645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Lee JY, Nam M, Son HY, Hyun K, Jang SY, Kim JW, et al. Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proc Natl Acad Sci USA. 2020;117:32433–42. https://doi.org/10.1073/pnas.2006828117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Nakamura S. Integrated pathophysiology of schizophrenia, major depression, and bipolar disorder as monoamine axon disorder. Front Biosci 2022;14:4. https://doi.org/10.31083/j.fbs1401004.

    Article  CAS  Google Scholar 

  213. Yamamoto H, Lee-Okada, Ikeda M, Nakamura T, Saito T, Takata A, et al. GWAS-identified bipolar disorder risk allele in the FADS1/2 gene region links mood episodes and unsaturated fatty acid metabolism in mutant mice. Mol Psychiatry. 2023;. https://doi.org/10.1038/s41380-023-01988-2.

  214. Pontel LB, Bueno-Costa A, Morellato AE, Carvalho Santos J, Roué G, Esteller M. Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing. Redox Biol. 2022;55:102408. https://doi.org/10.1016/j.redox.2022.102408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Chen L, Xie J. Ferroptosis-Suppressor-Protein 1: A potential neuroprotective target for combating ferroptosis. Mov Disord. 2020;35:400. https://doi.org/10.1002/mds.27990.

    Article  PubMed  Google Scholar 

  216. Vallerga CL, Zhang F, Fowdar J, McRae AF, Qi T, Nabais MF, et al. Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson’s disease. Nat Commun. 2020;11:1238. https://doi.org/10.1038/s41467-020-15065-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Itou M, Kawaguchi T, Taniguchi E, Sata M. Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol. 2013;19:2298–306. https://doi.org/10.3748/wjg.v19.i15.2298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 2017;20:1692–704. https://doi.org/10.1016/j.celrep.2017.07.055.

    Article  CAS  PubMed  Google Scholar 

  219. Turcot V, Bouchard L, Faucher G, Tchernof A, Deshaies Y, Pérusse L, et al. DPP4 gene DNA methylation in the omentum is associated with its gene expression and plasma lipid profile in severe obesity. Obesity. 2011;19:388–95. https://doi.org/10.1038/oby.2010.198.

    Article  CAS  PubMed  Google Scholar 

  220. Wang Z, Zhang Y, Fang J, Yu F, Heng D, Fan Y, et al. Decreased methylation level of H3K27me3 increases seizure susceptibility. Mol Neurobiol. 2017;54:7343–52. https://doi.org/10.1007/s12035-016-0197-4.

    Article  CAS  PubMed  Google Scholar 

  221. Cui X, Yun X, Sun M, Li R, Lyu X, Lao Y, et al. HMGCL-induced β-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility. Hepatol Int. 2023;17:377–92. https://doi.org/10.1007/s12072-022-10459-9.

    Article  PubMed  Google Scholar 

  222. Sharma S, Taliyan R. Targeting histone deacetylases: a novel approach in Parkinson’s disease. Park Dis. 2015;2015:303294. https://doi.org/10.1155/2015/303294.

    Article  Google Scholar 

  223. Logie E, Van Puyvelde B, Cuypers B, Schepers A, Berghmans H, Verdonck J, et al. Ferroptosis induction in multiple myeloma cells triggers DNA methylation and histone modification changes associated with cellular senescence. Int J Mol Sci. 2021; 22:https://doi.org/10.3390/ijms222212234.

  224. Tong ZB, Kim H, El Touny L, Simeonov A, Gerhold D. LUHMES dopaminergic neurons are uniquely susceptible to ferroptosis. Neurotox Res. 2022;40:1526–36. https://doi.org/10.1007/s12640-022-00538-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Cousu C, Mulot E, De Smet A, Formichetti S, Lecoeuche D, Ren J, et al. Germinal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells. Nat Commun. 2023;14:5695. https://doi.org/10.1038/s41467-023-41317-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Jiang Y, Mao C, Yang R, Yan B, Shi Y, Liu X, et al. EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes. Theranostics. 2017;7:3293–305. https://doi.org/10.7150/thno.19988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Wang P, Chen Q, Tang Z, Wang L, Gong B, Li M, et al. Uncovering ferroptosis in Parkinson’s disease via bioinformatics and machine learning, and reversed deducing potential therapeutic natural products. Front Genet. 2023;14:1231707. https://doi.org/10.3389/fgene.2023.1231707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Kim J, Zhao H, Dan J, Kim S, Hardikar S, Hollowell D, et al. Maternal Setdb1 Is required for meiotic progression and preimplantation development in mouse. PLoS Genet. 2016;12:e1005970. https://doi.org/10.1371/journal.pgen.1005970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Liu T, Xu P, Ke S, Dong H, Zhan M, Hu Q, et al. Histone methyltransferase SETDB1 inhibits TGF-β-induced epithelial-mesenchymal transition in pulmonary fibrosis by regulating SNAI1 expression and the ferroptosis signaling pathway. Arch Biochem Biophys. 2022;715:109087. https://doi.org/10.1016/j.abb.2021.109087.

    Article  CAS  PubMed  Google Scholar 

  230. Al Chiblak M, Steinbeck F, Thiesen HJ, Lorenz P. DUF3669, a “domain of unknown function” within ZNF746 and ZNF777, oligomerizes and contributes to transcriptional repression. BMC Mol Cell Biol. 2019;20:60. https://doi.org/10.1186/s12860-019-0243-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, et al. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell. 2011;144:689–702. https://doi.org/10.1016/j.cell.2011.02.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Yang Y, Bedford MT. Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2013;13:37–50. https://doi.org/10.1038/nrc3409.

    Article  CAS  PubMed  Google Scholar 

  233. Zhou L, Jia X, Shang Y, Sun Y, Liu Z, Liu J, et al. PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia. Mol Carcinog. 2023;62:1119–35. https://doi.org/10.1002/mc.23550.

    Article  CAS  PubMed  Google Scholar 

  234. Nho JH, Park MJ, Park HJ, Lee JH, Choi JH, Oh SJ, et al. Protein arginine methyltransferase-1 stimulates dopaminergic neuronal cell death in a Parkinson’s disease model. Biochem Biophys Res Commun. 2020;530:389–95. https://doi.org/10.1016/j.bbrc.2020.05.016.

    Article  CAS  PubMed  Google Scholar 

  235. Shukla S, Tekwani BL. Histone deacetylases inhibitors in neurodegenerative diseases, neuroprotection and neuronal differentiation. Front Pharmacol. 2020;11:537. https://doi.org/10.3389/fphar.2020.00537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Zhang M, Wang J, Li J, Kong F, Lin S. miR-101-3p improves neuronal morphology and attenuates neuronal apoptosis in ischemic stroke in young mice by downregulating HDAC9. Transl Neurosci. 2023;14:20220286. https://doi.org/10.1515/tnsci-2022-0286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Sanguigno L, Guida N, Anzilotti S, Cuomo O, Mascolo L, Serani A, et al. Stroke by inducing HDAC9-dependent deacetylation of HIF-1 and Sp1, promotes TfR1 transcription and GPX4 reduction, thus determining ferroptotic neuronal death. Int J Biol Sci. 2023;19:2695–710. https://doi.org/10.7150/ijbs.80735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Mazzocchi M, Wyatt SL, Mercatelli D, Morari M, Morales-Prieto N, Collins LM, et al. Gene co-expression analysis identifies histone deacetylase 5 and 9 expression in midbrain dopamine neurons and as regulators of neurite growth via bone morphogenetic protein signaling. Front Cell Dev Biol. 2019;7:191. https://doi.org/10.3389/fcell.2019.00191.

    Article  PubMed  PubMed Central  Google Scholar 

  239. Pastore D, Pacifici F, Capuani B, Palmirotta R, Dong C, Coppola A, et al. Sex-genetic interaction in the risk for cerebrovascular disease. Curr Med Chem. 2017;24:2687–99. https://doi.org/10.2174/0929867324666170417100318.

    Article  CAS  PubMed  Google Scholar 

  240. Bazan N, Bhattacharjee S, Kala-Bhattacharjee S, Ledet A, Mukherjee P. Elovanoids are neural resiliency epigenomic regulators targeting histone modifications, DNA methylation, tau phosphorylation, telomere integrity, senescence programming, and dendrite integrity. Res Sq. 2023;. https://doi.org/10.21203/rs.3.rs-3185942/v1.

  241. Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem. 2003;278:43807–17. https://doi.org/10.1074/jbc.M305841200.

    Article  CAS  PubMed  Google Scholar 

  242. Bazan NG. Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection. Mol Aspects Med. 2018;64:18–33. https://doi.org/10.1016/j.mam.2018.09.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Calandria JM, Sharp MW, Bazan NG. The docosanoid neuroprotectin D1 Induces TH-positive neuronal survival in a cellular model of Parkinson’s disease. Cell Mol Neurobiol. 2015;35:1127–36. https://doi.org/10.1007/s10571-015-0206-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Feng Z, Lin M, Wu R. The regulation of aging and longevity: a new and complex role of p53. Genes Cancer. 2011;2:443–52. https://doi.org/10.1177/1947601911410223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9:749–58. https://doi.org/10.1038/nrc2723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Rodriguez-Meira A, Norfo R, Wen S, Chédeville AL, Rahman H, O’Sullivan J, et al. Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution. Nat Genet. 2023;55:1531–41. https://doi.org/10.1038/s41588-023-01480-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Ng HH, Xu RM, Zhang Y, Struhl K. Ubiquitination of histone H2B by Rad6 is required for efficient Dot1-mediated methylation of histone H3 lysine 79. J Biol Chem. 2002;277:34655–7. https://doi.org/10.1074/jbc.C200433200.

    Article  CAS  PubMed  Google Scholar 

  248. Sun ZW, Allis CD. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature. 2002;418:104–8. https://doi.org/10.1038/nature00883.

    Article  CAS  PubMed  Google Scholar 

  249. Cole AJ, Dickson KA, Liddle C, Stirzaker C, Shah JS, Clifton-Bligh R, et al. Ubiquitin chromatin remodelling after DNA damage is associated with the expression of key cancer genes and pathways. Cell Mol Life Sci. 2021;78:1011–27. https://doi.org/10.1007/s00018-020-03552-5.

    Article  CAS  PubMed  Google Scholar 

  250. Wang S-J, Li D, Ou Y, Jiang L, Chen Y, Zhao Y, et al. Acetylation is crucial for p53-mediated ferroptosis and tumor suppression. Cell Rep. 2016;17:366–73. https://doi.org/10.1016/j.celrep.2016.09.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Yang Y, Ma Y, Li Q, Ling Y, Zhou Y, Chu K, et al. STAT6 inhibits ferroptosis and alleviates acute lung injury via regulating P53/SLC7A11 pathway. Cell Death Dis. 2022;13:530. https://doi.org/10.1038/s41419-022-04971-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Li S, Wang M, Wang Y, Guo Y, Tao X, Wang X, et al. p53-mediated ferroptosis is required for 1-methyl-4-phenylpyridinium-induced senescence of PC12 cells. Toxicol Vitro. 2021;73:105146. https://doi.org/10.1016/j.tiv.2021.105146.

    Article  CAS  Google Scholar 

  253. Zhao J, Jia Y, Mahmut D, Deik AA, Jeanfavre S, Clish CB, et al. Human hematopoietic stem cell vulnerability to ferroptosis. Cell. 2023;186:732–.e16. https://doi.org/10.1016/j.cell.2023.01.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Oki M, Aihara H, Ito T. Role of histone phosphorylation in chromatin dynamics and its implications in diseases. Subcell Biochem. 2007;41:319–36.

    PubMed  Google Scholar 

  255. Liu S, Yao S, Yang H, Liu S, Wang Y. Autophagy: regulator of cell death. Cell Death Dis. 2023;14:648. https://doi.org/10.1038/s41419-023-06154-8.

    Article  PubMed  PubMed Central  Google Scholar 

  256. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290:1717–21. https://doi.org/10.1126/science.290.5497.1717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Dai Y, Zhu C, Xiao W, Huang K, Wang X, Shi C, et al. Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth. J Clin Invest. 2023;133:e159941. https://doi.org/10.1172/jci159941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Chen W, Yang W, Zhang C, Liu T, Zhu J, Wang H, et al. Modulation of the p38 MAPK Pathway by anisomycin promotes ferroptosis of hepatocellular carcinoma through phosphorylation of H3S10. Oxid Med Cell Longev. 2022;2022:6986445. https://doi.org/10.1155/2022/6986445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12:1425. https://doi.org/10.1080/15548627.2016.1187366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–32. https://doi.org/10.1038/cr.2016.95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Jiang Y, Xie G, Alimujiang A, Xie H, Yang W, Yin F. et al. Protective effects of quercetin against MPP+-induced dopaminergic neurons Injury via the Nrf2 signaling pathway. Front Biosci. 2023;28:42. https://doi.org/10.31083/j.fbl2803042.

    Article  CAS  Google Scholar 

  262. Li L, Xie K, Xie H, Wang L, Li Z, Lu Q, et al. AURKB promotes colorectal cancer progression by triggering the phosphorylation of histone H3 at serine 10 to activate CCNE1 expression. Aging. 2024;16:8019–30. https://doi.org/10.18632/aging.205801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Komar D, Juszczynski P. Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy. Clin Epigenetics. 2020;12:147. https://doi.org/10.1186/s13148-020-00941-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Li B, Huang G, Zhang X, Li R, Wang J, Dong Z, et al. Increased phosphorylation of histone H3 at serine 10 is involved in Epstein-Barr virus latent membrane protein-1-induced carcinogenesis of nasopharyngeal carcinoma. BMC Cancer. 2013;13:124. https://doi.org/10.1186/1471-2407-13-124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Pacaud R, Cheray M, Nadaradjane A, Vallette FM, Cartron PF. Histone H3 phosphorylation in GBM: a new rationale to guide the use of kinase inhibitors in anti-GBM therapy. Theranostics. 2015;5:12–22. https://doi.org/10.7150/thno.8799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Makeyev EV, Maniatis T. Multilevel regulation of gene expression by microRNAs. Science. 2008;319:1789–90. https://doi.org/10.1126/science.1152326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33. https://doi.org/10.1016/j.cell.2009.01.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Angelopoulou E, Paudel YN, Piperi C. miR-124 and Parkinson’s disease: A biomarker with therapeutic potential. Pharmacol Res. 2019;150:104515. https://doi.org/10.1016/j.phrs.2019.104515.

    Article  CAS  PubMed  Google Scholar 

  269. Esteves M, Abreu R, Fernandes H, Serra-Almeida C, Martins PAT, Barão M, et al. MicroRNA-124-3p-enriched small extracellular vesicles as a therapeutic approach for Parkinson’s disease. Mol Ther. 2022;30:3176–92. https://doi.org/10.1016/j.ymthe.2022.06.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Wu L, Tian X, Zuo H, Zheng W, Li X, Yuan M, et al. miR-124-3p delivered by exosomes from heme oxygenase-1 modified bone marrow mesenchymal stem cells inhibits ferroptosis to attenuate ischemia-reperfusion injury in steatotic grafts. J Nanobiotechnol. 2022;20:196. https://doi.org/10.1186/s12951-022-01407-8.

    Article  CAS  Google Scholar 

  271. Zhang Y, Li Y. Long non-coding RNA NORAD contributes to the proliferation, invasion and EMT progression of prostate cancer via the miR-30a-5p/RAB11A/WNT/β-catenin pathway. Cancer Cell Int. 2020;20:571. https://doi.org/10.1186/s12935-020-01665-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Zhang H, He Y, Wang JX, Chen MH, Xu JJ, Jiang MH, et al. miR-30-5p-mediated ferroptosis of trophoblasts is implicated in the pathogenesis of preeclampsia. Redox Biol. 2020;29:101402. https://doi.org/10.1016/j.redox.2019.101402.

    Article  CAS  PubMed  Google Scholar 

  273. Vallelunga A, Iannitti T, Dati G, Capece S, Maugeri M, Tocci E, et al. Serum miR-30c-5p is a potential biomarker for multiple system atrophy. Mol Biol Rep. 2019;46:1661–6. https://doi.org/10.1007/s11033-019-04614-z.

    Article  CAS  PubMed  Google Scholar 

  274. Jayaprakash S, Le LTM, Sander B, Golas MM. Expression of the Neural REST/NRSF-SIN3 Transcriptional Corepressor complex as a target for small-molecule inhibitors. Mol Biotechnol. 2021;63:53–62. https://doi.org/10.1007/s12033-020-00283-7.

    Article  CAS  PubMed  Google Scholar 

  275. Nassar A, Satarker S, Gurram PC, Upadhya D, Fayaz SM, Nampoothiri M. Repressor Element-1 Binding Transcription Factor (REST) as a possible epigenetic regulator of neurodegeneration and microRNA-based therapeutic strategies. Mol Neurobiol. 2023;60:5557–77. https://doi.org/10.1007/s12035-023-03437-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Ma J, Li X, Fan Y, Yang D, Gu Q, Li D, et al. miR-494-3p promotes erastin-induced ferroptosis by targeting REST to activate the Interplay between SP1 and ACSL4 in Parkinson’s Disease. Oxid Med Cell Longev. 2022;2022:7671324. https://doi.org/10.1155/2022/7671324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Li L, Ren J, Pan C, Li Y, Xu J, Dong H, et al. Serum miR-214 serves as a biomarker for prodromal Parkinson’s disease. Front Aging Neurosci. 2021;13:700959. https://doi.org/10.3389/fnagi.2021.700959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Luo J, Song G, Chen N, Xie M, Niu X, Zhou S, et al. Ferroptosis contributes to ethanol-induced hepatic cell death via labile iron accumulation and GPx4 inactivation. Cell Death Discov. 2023;9:311. https://doi.org/10.1038/s41420-023-01608-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Rocha EM, Keeney MT, Di Maio R, De Miranda BR, Greenamyre JT. LRRK2 and idiopathic Parkinson’s disease. Trends Neurosci. 2022;45:224–36. https://doi.org/10.1016/j.tins.2021.12.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Ye H, Robak LA, Yu M, Cykowski M, Shulman JM. Genetics and pathogenesis of Parkinson’s syndrome. Annu Rev Pathol. 2023;18:95–121. https://doi.org/10.1146/annurev-pathmechdis-031521-4145.

    Article  CAS  PubMed  Google Scholar 

  281. Simuni T, Chahine LM, Poston K, Brumm M, Buracchio T, Campbell M, et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024;23:178–90. https://doi.org/10.1016/s1474-4422(23)00405-2.

    Article  CAS  PubMed  Google Scholar 

  282. Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol. 2021;20:385–97. https://doi.org/10.1016/s1474-4422(21)00030-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Bae YJ, Kim JM, Sohn CH, Choi JH, Choi BS, Song YS, et al. Imaging the substantia nigra in Parkinson disease and other Parkinsonian syndromes. Radiology. 2021;300:260–78. https://doi.org/10.1148/radiol.2021203341.

    Article  PubMed  Google Scholar 

  284. Meissner WG, Remy P, Giordana C, Maltête D, Derkinderen P, Houéto JL, et al. Trial of lixisenatide in early Parkinson’s disease. N Engl J Med. 2024;390:1176–85. https://doi.org/10.1056/NEJMoa2312323.

    Article  CAS  PubMed  Google Scholar 

  285. Zhang D, Deng Y, Kukanja P, Agirre E, Bartosovic M, Dong M, et al. Spatial epigenome-transcriptome co-profiling of mammalian tissues. Nature. 2023;616:113–22. https://doi.org/10.1038/s41586-023-05795-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Mendes Serrão E, Klug M, Moloney BM, Jhaveri A, Lo Gullo R, Pinker K, et al. Current status of cancer genomics and imaging phenotypes: what radiologists need to know. Radiol Imaging Cancer. 2023;5:e220153. https://doi.org/10.1148/rycan.220153.

    Article  PubMed  PubMed Central  Google Scholar 

  287. Schirinzi T, Maftei D, Passali FM, Grillo P, Zenuni H, Mascioli D, et al. Olfactory neuron prokineticin-2 as a potential target in Parkinson’s disease. Ann Neurol. 2023;93:196–204. https://doi.org/10.1002/ana.26526.

    Article  CAS  PubMed  Google Scholar 

  288. Trentin S, Oliveira BSF, Borges YFF, Rieder CRM. Evaluation of the complete Sniffin Sticks Test versus its subtests in differentiating Parkinson’s disease patients from healthy controls. Arq Neuropsiquiatr. 2022;80:908–13. https://doi.org/10.1055/s-0042-1755268.

    Article  PubMed  PubMed Central  Google Scholar 

  289. Hill DR, Huters AD, Towne TB, Reddy RE, Fogle JL, Voight EA, et al. Parkinson’s disease: advances in treatment and the syntheses of various classes of pharmaceutical drug substances. Chem Rev. 2023;123:13693–712. https://doi.org/10.1021/acs.chemrev.3c00479.

    Article  CAS  PubMed  Google Scholar 

  290. Li J, Hao D, Wang L, Wang H, Wang Y, Zhao Z, et al. Epigenetic targeting drugs potentiate chemotherapeutic effects in solid tumor therapy. Sci Rep. 2017;7:4035. https://doi.org/10.1038/s41598-017-04406-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Morel D, Jeffery D, Aspeslagh S, Almouzni G, Postel-Vinay S. Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise. Nat Rev Clin Oncol. 2020;17:91–107. https://doi.org/10.1038/s41571-019-0267-4.

    Article  CAS  PubMed  Google Scholar 

  292. Burtscher J, Moraud EM, Malatesta D, Millet GP, Bally JF, Patoz A. Exercise and gait/movement analyses in treatment and diagnosis of Parkinson’s Disease. Ageing Res Rev. 2024;93:102147. https://doi.org/10.1016/j.arr.2023.102147.

    Article  CAS  PubMed  Google Scholar 

  293. Ernst M, Folkerts AK, Gollan R, Lieker E, Caro-Valenzuela J, Adams A, et al. Physical exercise for people with Parkinson’s disease: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2023;1:Cd013856. https://doi.org/10.1002/14651858.CD013856.pub2.

    Article  PubMed  Google Scholar 

  294. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575–80. https://doi.org/10.1038/s41586-019-1678-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Pan RY, He L, Zhang J, Liu X, Liao Y, Gao J, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metab. 2022;34:634–.e6. https://doi.org/10.1016/j.cmet.2022.02.013.

    Article  CAS  PubMed  Google Scholar 

  296. Zou W, Gao F, Meng Z, Cai X, Chen W, Zheng Y, et al. Lactic acid responsive sequential production of hydrogen peroxide and consumption of glutathione for enhanced ferroptosis tumor therapy. J Colloid Interface Sci. 2024;663:787–800. https://doi.org/10.1016/j.jcis.2024.03.001.

    Article  CAS  PubMed  Google Scholar 

  297. Li J, Chen L, Qin Q, Wang D, Zhao J, Gao H, et al. Upregulated hexokinase 2 expression induces the apoptosis of dopaminergic neurons by promoting lactate production in Parkinson’s disease. Neurobiol Dis. 2022;163:105605. https://doi.org/10.1016/j.nbd.2021.105605.

    Article  CAS  PubMed  Google Scholar 

  298. Yu Y, Huang X, Liang C, Zhang P. Evodiamine impairs HIF1A histone lactylation to inhibit Sema3A-mediated angiogenesis and PD-L1 by inducing ferroptosis in prostate cancer. Eur J Pharmacol. 2023;957:176007. https://doi.org/10.1016/j.ejphar.2023.176007.

    Article  CAS  PubMed  Google Scholar 

  299. Pickar-Oliver A, Gersbach CA. The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol. 2019;20:490–507. https://doi.org/10.1038/s41580-019-0131-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Nuñez JK, Chen J, Pommier GC, Cogan JZ, Replogle JM, Adriaens C, et al. Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing. Cell. 2021;184:2503–.e17. https://doi.org/10.1016/j.cell.2021.03.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This article was supported by the National Natural Science Foundation of China (32371187, 32471049), Excellent Innovative Team of Shandong Province (2020KJK007), and Taishan Scholars Construction Project, Shandong.

Author information

Authors and Affiliations

  1. Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases and State Key Disciplines: Physiology, Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China

    Xiao-die Gao, Jian-e Ding & Hua-min Xu

  2. Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China

    Jun-xia Xie & Hua-min Xu

Authors
  1. Xiao-die Gao
    View author publications

    Search author on:PubMed Google Scholar

  2. Jian-e Ding
    View author publications

    Search author on:PubMed Google Scholar

  3. Jun-xia Xie
    View author publications

    Search author on:PubMed Google Scholar

  4. Hua-min Xu
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Jun-xia Xie or Hua-min Xu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, Xd., Ding, Je., Xie, Jx. et al. Epigenetic regulation of iron metabolism and ferroptosis in Parkinson’s disease: Identifying novel epigenetic targets. Acta Pharmacol Sin 46, 2075–2092 (2025). https://doi.org/10.1038/s41401-025-01499-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41401-025-01499-6

Keywords

This article is cited by

Search

Advanced search

Quick links