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Sphingosine-1-phosphate (S1P), a ubiquitous bioactive lipid, has emerged as a key therapeutic target in MS due to its dual roles in immune regulation and neuroprotection; however, the therapeutic efficacy of current S1P-based therapies in remyelination remains unclear. This systematic review evaluated in vivo studies up to July 2025, in accordance with PRISMA guidelines, to assess the efficacy of S1P modulators on remyelination in mammalian models of demyelination. A comprehensive search across three databases identified 24 eligible studies that investigated S1P receptor (S1PR) modulation in both acute and chronic models of demyelination, with or without immune-mediated components. Fingolimod was the most extensively studied compound (16 studies). Of the 18 studies assessing demyelination outcomes, S1P modulation consistently attenuated myelin loss and oligodendrocyte depletion. In contrast, remyelination outcomes were inconsistent: among 15 studies assessing repair, most reported no significant enhancement. While fingolimod showed limited evidence on remyelination, more promising effects were observed with selective S1PR1\/5 modulators such as siponimod and ponesimod. Overall, current evidence supports a model in which S1P modulators act primarily through S1PR1-mediated immunomodulation and S1PR5-associated oligodendroglial protection, preserving oligodendrocyte lineage cells rather than driving terminal differentiation or de novo remyelination. Several compounds displayed bell-shaped dose\u2013response patterns, highlighting the importance of dosing and treatment paradigms. Collectively, these findings indicate S1PR-based therapies primarily limit demyelination, with limited evidence of remyelination, emphasising the need for more efficacious S1P modulators to improve MS outcomes.<\/jats:p>","DOI":"10.1007\/s10571-026-01748-0","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T07:38:06Z","timestamp":1781077086000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Sphingosine 1-phosphate Modulators on Central Remyelination: A Systematic Review of Animal Models"],"prefix":"10.1007","volume":"46","author":[{"given":"Harley","family":"Vu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson","family":"George","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4320-2855","authenticated-orcid":false,"given":"Junhua","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"issue":"8","key":"1748_CR1","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1177\/1352458511400476","volume":"17","author":"S Al-Izki","year":"2011","unstructured":"Al-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D (2011) Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. 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