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CD38 dysregulation and gene variation is reported in neurodegenerative conditions such as Parkinson's disease (PD) and Alzheimer's disease (AD), highlighting the need to better understand CD38 biology within the brain. Here, we demonstrate enrichment of\n                    <jats:italic>Cd38<\/jats:italic>\n                    in midbrain astrocytes and describe how CD38 deficiency influences brain metabolism, astrocytic gene expression, and bioenergetics. We demonstrate increased NAD content, decreased NAM content, and increased NAD\/NAM in the midbrain and striatum of CD38\u2010deficient (\n                    <jats:italic>Cd38<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    ) mice, indicating the dependence on CD38 for NAD to NAM conversion in the brain. RNA\u2010sequencing of isolated astrocytes revealed numerous differentially expressed genes in\n                    <jats:italic>Cd38<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    and\n                    <jats:italic>Cd38<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice, with alterations in mitochondrial, metabolic, senescence\u2010related, astrocyte reactivity, and other genes involved in PD and AD etiology. Furthermore, functional metabolic analysis of midbrain revealed changes in pyruvate oxidation, age\u2010dependent increase of citrate synthase (CS) activity, and reduction of cytochrome c oxidase\u2010to\u2010CS ratio in\n                    <jats:italic>Cd38<\/jats:italic>\n                    deficiency. These findings identify a novel role for astrocytes in the regulation of CD38\u2010dependent NAD\/NAM homeostasis in the brain and provide a framework for future studies evaluating the relationship between CD38 dysfunction, aging, and vulnerability of neuronal populations in neurodegenerative disease. Importantly, these studies underscore the necessity to better resolve the impact of CD38 deficiency on brain metabolism, considering ongoing clinical trials and discussions related to the use of CD38 modulators for the treatment of cancers, age\u2010related decline, and neurodegenerative disease.\n                  <\/jats:p>","DOI":"10.1002\/glia.70112","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T11:36:47Z","timestamp":1765885007000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel Roles for the Ectoenzyme\n                    <scp>CD38<\/scp>\n                    in the Maintenance of Transcriptional and Metabolic Homeostasis in Astrocytes"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3034-5829","authenticated-orcid":false,"given":"S.","family":"Basak","sequence":"first","affiliation":[{"name":"School of Neuroscience, Virginia Tech  Blacksburg Virginia USA"},{"name":"Translational Biology Medicine and Health Graduate Program, Virginia Tech  Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5491-1630","authenticated-orcid":false,"given":"A. 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