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However, the cellular changes and underlying molecular mechanisms within the diabetic spinal cord are less clear. By using a rat model of type 1 diabetes (T1D), we noted an extensive and irreversible spinal astrocyte degeneration at an early stage of T1D, which is highly associated with the chronification of PDN. Molecularly, acetylation of astrocytic signal transducer and activator of transcription\u20103 (STAT3) that is essential for maintaining the homeostatic astrocytes population was significantly impaired in the T1D model, resulting in a dramatic loss of spinal astrocytes and consequently promoting pain hypersensitivity. Mechanistically, class IIa histone deacetylase, HDAC5 were aberrantly activated in spinal astrocytes of diabetic rats, which promoted STAT3 deacetylation by direct protein\u2013protein interactions, leading to the PDN phenotypes. Restoration of STAT3 signaling or inhibition of HDAC5 rescued astrocyte deficiency and attenuated PDN in the T1D model. Our work identifies the inhibitory axis of HDAC5\u2010STAT3 induced astrocyte deficiency as a key mechanism underlying the pathogenesis of the diabetic spinal cord that paves the way for potential therapy development for PDN.<\/jats:p>","DOI":"10.1002\/glia.24328","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T11:38:01Z","timestamp":1672313881000},"page":"1099-1119","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Histone deacetylase 5\u2010induced deficiency of signal transducer and activator of transcription\u20103 acetylation contributes to spinal astrocytes degeneration in painful diabetic neuropathy"],"prefix":"10.1002","volume":"71","author":[{"given":"Tingting","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Anaesthesiology, Laboratory and Clinical Research Institute for Pain The University of Hong Kong  Hong Kong Hong Kong SAR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, Laboratory and Clinical Research Institute for Pain The University of Hong Kong  Hong Kong Hong Kong SAR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong\u2010long","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, Laboratory and Clinical Research Institute for Pain The University of Hong Kong  Hong Kong Hong Kong SAR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology The University of Hong Kong\u2010Shenzhen Hospital  Shenzhen China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanley","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, Laboratory and Clinical Research Institute for Pain The University of Hong Kong  Hong Kong Hong Kong SAR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng\u2010yuan","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Medicine, State Key Laboratory of Pharmaceutical Biotechnology The University of Hong Kong  Hong Kong Hong Kong SAR"},{"name":"Department of Anesthesiology Affiliated Hospital of Guangdong Medical University  Zhanjiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9307-2235","authenticated-orcid":false,"given":"Jessica Aijia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience City University of Hong Kong, Tat Chee Avenue  Kowloon Hong Kong SAR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi\u2010wai","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, Laboratory and Clinical Research Institute for Pain The University of Hong Kong  Hong Kong Hong Kong SAR"},{"name":"Department of Anaesthesiology The University of Hong Kong\u2010Shenzhen Hospital  Shenzhen China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.20678"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0278-5846(03)00160-x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01412-16"},{"issue":"11","key":"e_1_2_9_5_1","first-page":"3561","article-title":"Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. 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