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Satellite glial cells (SGCs), critical for maintaining dorsal root ganglion (DRG) homeostasis, undergo significant structural and functional changes under pathological conditions. This study investigated the role of galactosylceramide (GalCer), a key sphingolipid, in SGC dysfunction and neuron\u2013glia interactions during DPN progression. Using a rat model of PDPN, we employed single-cell RNA sequencing (scRNA-seq), targeted mass spectrometry, and immunofluorescence analysis. The PDPN group exhibited transcriptional activation and structural reorganization of SGCs, characterized by increased SGC abundance and glial activation, evidenced by elevated Gfap expression. Functional enrichment analyses revealed disruptions in sphingolipid metabolism, including marked reductions in GalCer levels. Subclustering identified vulnerable SGC subsets, such as Cluster a, with dysregulated lipid metabolism. The depletion of GalCer impaired SGC-neuron communication, destabilizing DRG homeostasis and amplifying neurodegeneration and neuropathic pain. These findings demonstrate that GalCer depletion is a central mediator of SGC dysfunction in PDPN, disrupting neuron\u2013glia interactions and exacerbating neuropathic pain. This study provides novel insights into the molecular mechanisms of DPN progression and identifies GalCer metabolism as a potential therapeutic target.<\/jats:p>","DOI":"10.3390\/cells14060393","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:05:46Z","timestamp":1741331146000},"page":"393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Role of Galactosylceramide Metabolism in Satellite Glial Cell Dysfunction and Neuron\u2013Glia Interactions in Painful Diabetic Peripheral Neuropathy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2469-6933","authenticated-orcid":false,"given":"Xin","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Shanghai Ninth People\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shanghai Ninth People\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shanghai Ninth People\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2564-481X","authenticated-orcid":false,"given":"Chenlong","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shanghai Ninth People\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shanghai Ninth People\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9632-6424","authenticated-orcid":false,"given":"Wenchuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shanghai Ninth People\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/S2213-8587(19)30081-6","article-title":"Diabetic peripheral neuropathy: Advances in diagnosis and strategies for screening and early intervention","volume":"7","author":"Selvarajah","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.neuron.2017.02.005","article-title":"New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain","volume":"93","author":"Feldman","year":"2017","journal-title":"Neuron"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1161\/CIRCULATIONAHA.106.621854","article-title":"Advanced glycation end products: Sparking the development of diabetic vascular injury","volume":"114","author":"Goldin","year":"2006","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1210\/er.2003-0019","article-title":"Oxidative stress in the pathogenesis of diabetic neuropathy","volume":"25","author":"Vincent","year":"2004","journal-title":"Endocr. 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