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The drug, acting on the sphingosine\u20101\u2010phosphate pathway, is involved in a plethora of processes and, to date, its mechanism of action is not completely understood.<\/jats:p><jats:p>Recently, it has been demonstrated that Fingolimod increases the expression of transcription factor <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A2 in murine brain. <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A2 belongs to nuclear receptor family 4, group A (<jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A) along with <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A1 and <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A3. The role of <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A2 in the pathogenesis of multiple sclerosis is already known and supported by its down\u2010regulation observed in blood obtained from patients with <jats:styled-content style=\"fixed-case\">RRMS<\/jats:styled-content> compared with healthy controls (<jats:styled-content style=\"fixed-case\">HCs<\/jats:styled-content>). It is notable that <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A2 impairment is reversed in patients with <jats:styled-content style=\"fixed-case\">RRMS<\/jats:styled-content> during pregnancy, which represents a transitory state of immune tolerance, associated with reduced disease activity. An inverse correlation between <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A2 gene expression levels and clinical parameters indicates that more aggressive forms of the disease are characterized by lower levels of <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Gene expression levels of <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A in blood obtained from <jats:styled-content style=\"fixed-case\">HCs<\/jats:styled-content>, treatment\u2010naive (T0) and Fingolimod\u2010treated patients with <jats:styled-content style=\"fixed-case\">RRMS<\/jats:styled-content> were evaluated to determine their contribution to drug response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Gene expression levels of <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A were down\u2010regulated in T0 patients compared with <jats:styled-content style=\"fixed-case\">HCs<\/jats:styled-content>. Patients treated with Fingolimod for &gt;2\u00a0years were characterized by higher levels of <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A2 compared with the T0 group, approaching those of <jats:styled-content style=\"fixed-case\">HCs<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A1 and <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A3 levels were not altered.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Involvement of the <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A family in the pathogenesis of multiple sclerosis and a role of Fingolimod in the recovery from <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>4A2 deficit can be hypothesized based on our 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