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Among the sphingosine 1\u2010phosphate receptors (S1PRs) family, S1PR1 is a highly expressed subtype in the central nervous system and has gained rapid attention as an important mediator of pathophysiological processes in the brain and the retina. Our recent study showed that mice treated orally with siponimod drug exerted neuroprotection via modulation of neuronal S1PR1 in experimental glaucoma. This study identified the molecular signaling pathway modulated by S1PR1 activation with siponimod treatment in RGCs in glaucomatous injury. We investigated the critical neuroprotective signaling pathway in vivo using mice deleted for S1PR1 in RGCs. Our results showed marked upregulation of the apoptotic pathway was associated with decreased Akt and Erk1\/2 activation levels in the retina in glaucoma conditions. Activation of S1PR1 with siponimod treatment significantly increased neuroprotective Akt and Erk1\/2 activation and attenuated the apoptotic signaling via suppression of c\u2010Jun\/Bim cascade and by increasing Bad phosphorylation. Conversely, deletion of S1PR1 in RGCs significantly increased the apoptotic cells in the ganglion cell layer in glaucoma and diminished the neuroprotective effects of siponimod treatment on Akt\/Erk1\/2 activation, c\u2010Jun\/Bim cascade, and Bad phosphorylation. Our data demonstrated that activation of S1PR1 in RGCs induces crucial neuroprotective signaling that suppresses the proapoptotic c\u2010Jun\/Bim cascade and increases antiapoptotic Bad phosphorylation. Our findings suggest that S1PR1 is a potential therapeutic target for neuroprotection of RGCs in glaucoma.<\/jats:p>","DOI":"10.1096\/fj.202201346r","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T10:19:16Z","timestamp":1671099556000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["<scp>S1PR1<\/scp>\n                    signaling attenuates apoptosis of retinal ganglion cells via modulation of\n                    <scp>cJun<\/scp>\n                    \/Bim cascade and Bad phosphorylation in a mouse model of glaucoma"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0997-0196","authenticated-orcid":false,"given":"Devaraj","family":"Basavarajappa","sequence":"first","affiliation":[{"name":"Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  North Ryde Sydney New South Wales 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