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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,2,6]]},"abstract":"<jats:p>\n                    The N6-methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) modification of RNA is an emerging epigenetic regulatory mechanism that has been shown to participate in various pathophysiological processes. However, its involvement in modulating neuropathic pain is still poorly understood. In this study, we elucidate a functional role of the m\n                    <jats:sup>6<\/jats:sup>\n                    A demethylase alkylation repair homolog 5 (ALKBH5) in modulating trigeminal-mediated neuropathic pain. Peripheral nerve injury selectively upregulated the expression level of ALKBH5 in the injured trigeminal ganglion (TG) of rats. Blocking this upregulation in injured TGs alleviated trigeminal neuropathic pain, while mimicking the upregulation of ALKBH5 in intact TG neurons sufficiently induced pain-related behaviors. Mechanistically, histone deacetylase 11 downregulation induced by nerve injury increases histone H3 lysine 27 acetylation (H3K27ac), facilitating the binding of the transcription factor forkhead box protein D3 (FOXD3) to the\n                    <jats:italic>Alkbh5<\/jats:italic>\n                    promoter and promoting\n                    <jats:italic>Alkbh5<\/jats:italic>\n                    transcription. The increased ALKBH5 erases m\n                    <jats:sup>6<\/jats:sup>\n                    A sites in\n                    <jats:italic>Htr3a<\/jats:italic>\n                    messenger RNA (mRNA), resulting in an inability of YT521-B homology domain 2 (YTHDF2) to bind to\n                    <jats:italic>Htr3a<\/jats:italic>\n                    mRNA, thus causing an increase in 5-HT3A protein expression and 5-HT3 channel currents. Conversely, blocking the increased expression of ALKBH5 in the injured TG destabilizes nerve injury\u2013induced 5-HT3A upregulation and reverses mechanical allodynia, and the effect can be blocked by 5-HT3A knockdown. Together, FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain through m\n                    <jats:sup>6<\/jats:sup>\n                    A-dependent stabilization of\n                    <jats:italic>Htr3a<\/jats:italic>\n                    mRNA in TG neurons. This mechanistic understanding may advance the discovery of new therapeutic targets for neuropathic pain management.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2312861121","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T15:00:21Z","timestamp":1706540421000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":25,"title":["FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain via m\n                    <sup>6<\/sup>\n                    A-dependent stabilization of 5-HT3A mRNA in sensory neurons"],"prefix":"10.1073","volume":"121","author":[{"given":"Zitong","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Physiology and Neurobiology, Suzhou Medical College of Soochow University, Suzhou 215123, People\u2019s Republic of China"},{"name":"Centre for Ion Channelopathy, Soochow University, Suzhou 215123, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9554-9658","authenticated-orcid":false,"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinical Research Center of Neurological Disease, Department of Geriatrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People\u2019s Republic of China"},{"name":"Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou 215123, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoupeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology, Suzhou Medical College of Soochow University, Suzhou 215123, People\u2019s Republic of China"},{"name":"Centre for Ion Channelopathy, Soochow University, Suzhou 215123, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renfei","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology, Suzhou Medical College of Soochow University, Suzhou 215123, People\u2019s Republic of China"},{"name":"Centre for Ion Channelopathy, Soochow University, Suzhou 215123, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6141-5149","authenticated-orcid":false,"given":"Yu","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology, Suzhou Medical College of Soochow University, Suzhou 215123, People\u2019s Republic of China"},{"name":"Centre for Ion Channelopathy, Soochow University, Suzhou 215123, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology, Suzhou Medical College of Soochow University, Suzhou 215123, People\u2019s Republic of China"},{"name":"Centre for Ion Channelopathy, Soochow University, Suzhou 215123, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0961-2671","authenticated-orcid":false,"given":"Dongsheng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Institute of Regenerative Biology and Medicine, Helmholtz Zentrum M\u00fcnchen, Munich 81377, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology, Suzhou Medical College of Soochow University, Suzhou 215123, People\u2019s Republic of China"},{"name":"Centre for Ion Channelopathy, Soochow University, Suzhou 215123, People\u2019s Republic of 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