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Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor\u2010bearing immunocompetent mice, a clinically relevant dose of FTY720\/Fingolimod that targets sphingosine\u20101\u2010phosphate receptor 1 (S1PR1), alleviated paclitaxel\u2010induced neuropathic pain. FTY720 also significantly attenuated paclitaxel\u2010stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte\u2010secreted synaptogenic protein Sparcl1\/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti\u2010tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P\/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.<\/jats:p>","DOI":"10.1096\/fj.202401277r","type":"journal-article","created":{"date-parts":[[2024,8,10]],"date-time":"2024-08-10T04:59:53Z","timestamp":1723265993000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["FTY720\/Fingolimod mitigates paclitaxel\u2010induced Sparcl1\u2010driven neuropathic pain and breast cancer progression"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8069-6452","authenticated-orcid":false,"given":"Sandeep K.","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3132-4203","authenticated-orcid":false,"given":"Cynthia","family":"Weigel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2880-0301","authenticated-orcid":false,"given":"Ryan D. 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