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At present, there are no specific treatments available. Sphingolipid pathway is a key player in the endothelial barrier integrity; and is mediated through the five sphingosine\u20101\u2010phosphate receptors (S1PR1\u2010S1PR5). Signaling through S1PR2 promotes barrier disruption; and in Dengue virus (DENV)\u2010infection, there is overexpression of this receptor. Fingolimod (FTY720) is a specific agonist that targets the remaining barrier\u2010protective S1P receptors, without targeting S1PR2. In the present study, we explored whether FTY720 treatment can alleviate DENV\u2010induced endothelial hyperpermeability. In functional assays, in both <jats:italic>in vitro<\/jats:italic> systems and in AG129 animal models, FTY720 treatment was found effective. Upon treatment, there was complete restoration of the monolayer integrity in DENV serotype 2\u2010infected human microvascular endothelial cells (HMEC\u20101). At the molecular level, the treatment reversed activation of the S1P pathway. It significantly reduced the phosphorylation of the key molecules such as PTEN, RhoA, and VE\u2010Cadherin; and also, the expression levels of S1PR2. In DENV2\u2010infected AG129 mice treated with FTY720, there was significant improvement in weight gain, in overall clinical symptoms, and in survival. Whereas 100% of the DENV2\u2010infected, untreated animals died by day\u201010 post\u2010infection, 70% of the FTY720\u2010treated animals were alive; and at the end of the 15\u2010day post\u2010infection observation period, 30% of them were still surviving. There was a significant reduction in the Evan's\u2010blue dye permeability in the organs of FTY720\u2010treated, DENV\u20102 infected animals; and also improvement in the hemogram, with complete restoration of thrombocytopenia and hepatic function. Our results show that the FDA\u2010approved molecule Fingolimod (FTY720) is a promising therapeutic intervention in severe dengue.<\/jats:p>","DOI":"10.1002\/iub.2795","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T11:19:08Z","timestamp":1701343148000},"page":"267-285","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Fingolimod (<scp>FTY720<\/scp>), an <scp>FDA<\/scp>\u2010approved sphingosine 1\u2010phosphate (<scp>S1P<\/scp>) receptor agonist, restores endothelial hyperpermeability in cellular and animal models of dengue virus serotype 2 infection"],"prefix":"10.1002","volume":"76","author":[{"given":"Ayan","family":"Modak","sequence":"first","affiliation":[{"name":"Molecular Virology Laboratory Rajiv Gandhi Centre for Biotechnology (RGCB)  Thiruvananthapuram India"},{"name":"Regional Centre for Biotechnology (RCB), NCR Biotech Science Cluster  Faridabad Haryana (NCR 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