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Epilepsy often coexists with cardiovascular disease, cognitive dysfunction, depression, etc., which seriously affects the patient's quality of life. Although our understanding of epilepsy has advanced, the pathophysiological mechanisms leading to epileptogenesis, drug resistance, and associated comorbidities remain largely unknown. The use of newer antiepileptic drugs has increased, but this has not improved overall outcomes. We need to deeply study the pathogenesis of epilepsy and find drugs that can not only prevent the epileptogenesis and interfere with the process of epileptogenesis but also treat epilepsy comorbidities. Sphingosine\u20101\u2010phosphate (S1P) is an important lipid molecule. It not only forms the basis of cell membranes but is also an important bioactive mediator. It can not only act as a second messenger in cells to activate downstream signaling pathways but can also exert biological effects by being secreted outside cells and binding to S1P receptors on the cell membrane. Fingolimod (FTY720) is the first S1P receptor modulator developed and approved for the treatment of multiple sclerosis. More and more studies have proven that the S1P signaling pathway is closely related to epilepsy, drug\u2010resistant epilepsy, epilepsy comorbidities, or other epilepsy\u2010causing diseases. However, there is much controversy over the role of certain natural molecules in the pathway and receptor modulators (such as FTY720) in epilepsy. Here, we summarize and analyze the role of the S1P signaling pathway in epilepsy, provide a basis for finding potential therapeutic targets and\/or epileptogenic biomarkers, analyze the reasons for these controversies, and put forward our opinions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Plain Language Summary<\/jats:title><jats:p>This article combines the latest research literature at home and abroad to review the sphingosine 1\u2010phosphate signaling pathway and epileptogenesis, drug\u2010resistant epilepsy, epilepsy comorbidities, other diseases that can cause epilepsy, as well as the sphingosine\u20101\u2010phosphate signaling pathway regulators and epilepsy, with the expectation of providing a certain theoretical basis for finding potential epilepsy treatment targets and\/or epileptogenic biomarkers in the sphingosine\u20101\u2010phosphate signaling pathway.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.13112","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T13:39:02Z","timestamp":1735306742000},"page":"55-73","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The sphingosine\u20101\u2010phosphate signaling pathway (sphingosine\u20101\u2010phosphate and its receptor, sphingosine kinase) and epilepsy"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7429-1932","authenticated-orcid":false,"given":"Lin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology Affiliated Hospital of Jining Medical University  Jining City China"},{"name":"Epilepsy Center Affiliated Hospital of Jining Medical University  Jining City China"},{"name":"The Chinese University of Hong Kong, Department of Medicine and Therapeutics The Chinese University of Hong Kong, Central Ave  Hong Kong Hong Kong"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingxia","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Neurology Affiliated Hospital of Jining Medical University  Jining City China"},{"name":"Epilepsy Center Affiliated Hospital of Jining Medical University  Jining City China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyi","family":"Leng","sequence":"additional","affiliation":[{"name":"The Chinese University of Hong Kong, Department of Medicine and Therapeutics The Chinese University of Hong Kong, Central Ave  Hong Kong Hong Kong"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2594-4775","authenticated-orcid":false,"given":"Howan","family":"Leung","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital 7\/F Clinical Science Building, Prince of Wales Hospital  Hong Kong Hong 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