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Among disease-modifying therapies, sphingosine 1-phosphate (S1P) receptor (S1PR) modulators such as fingolimod, also known as FTY720, have been shown to exert therapeutic effects through direct CNS actions at S1PRs (e.g. S1P1) expressed by astrocytes, beyond the originally proposed mechanism action of lymphocyte sequestration. This review highlights the emerging evidence linking S1P signaling to the vitamin B12 pathway, including transcobalamin 2 (TCN2) and CD320. Functional interaction between S1P1 signaling and CD320 expression was discovered by examining gene expression changes in immediate-early astrocytes (ieAstrocytes), the primary CNS cell type activated in response to neuroinflammatory stimuli. This discovery led to the identification of the physical interaction between fingolimod\/sphingosine and TCN2 and the potentiation of CD320 internalization by this complex. These findings underscore the importance of CNS vitamin B12 levels in MS and likely other neurological diseases and help to explain the long-appreciated shared neurological symptoms between vitamin B12 deficiency and MS. Future research should investigate therapeutic strategies targeting the crosstalk between the sphingolipid and vitamin B12 pathways to enhance CNS vitamin B12 availability, which can promote neuroprotection in MS and related diseases.<\/jats:p>","DOI":"10.1093\/intimm\/dxaf058","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T12:27:05Z","timestamp":1758716825000},"page":"163-171","source":"Crossref","is-referenced-by-count":0,"title":["Neuroprotective crosstalk from vitamin B12 and sphingolipid signaling pathways in therapy for multiple sclerosis"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7462-3006","authenticated-orcid":false,"given":"Yasuyuki","family":"Kihara","sequence":"first","affiliation":[{"name":"Center for Neurologic Diseases, Sanford Burnham Prebys Medical Discovery Institute , 10901 North Torrey Pines Road, La Jolla, CA 92037 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