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Melatonin abrogates activation of hepatic stellate cells (HSCs) and attenuates different profibrogenic pathways in animal models of fibrosis, but it is unknown if protection associates with its inhibitory effect on the SphK1\/S1P axis. Mice in treatment groups received carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) 5 \u03bcL\u00a0g<jats:sup>\u22121<\/jats:sup> body wt i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg\u00a0kg<jats:sup>\u22121<\/jats:sup>\u00a0day<jats:sup>\u22121<\/jats:sup> i.p, beginning 2 weeks after the start of CCl<jats:sub>4<\/jats:sub> administration. At both 4 and 6 weeks following CCl<jats:sub>4<\/jats:sub> treatment, liver mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production, and expression of S1P receptor (S1PR)1, S1PR3 and acid sphingomyelinase (ASMase) were significantly elevated. However, there was a decreased expression of S1PR2 and S1P lyase (S1PL). Melatonin attenuated liver fibrosis, as shown by a significant inhibition of the expression of \u03b1\u2010smooth muscle actin (\u03b1\u2010SMA), transforming growth factor (TGF)\u2010\u03b2 and collagen (Col) \u0399. Furthermore, melatonin inhibited S1P production, lowered expression of SphK1, S1PR1, SP1R3, and ASMase, and increased expression of S1PL. Melatonin induced a reversal of activated human HSCs cell line LX2, as evidenced by a reduction in \u03b1\u2010SMA, TGF\u2010\u03b2, and Col I expression. Melatonin\u2010treated cells also exhibited an inhibition of the SphK1\/S1P axis. Antifibrogenic effect of SphK1 inhibition was confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in liver fibrogenesis. \u00a9 2016 BioFactors, 43(2):272\u2013282, 2017<\/jats:p>","DOI":"10.1002\/biof.1342","type":"journal-article","created":{"date-parts":[[2016,11,1]],"date-time":"2016-11-01T14:43:23Z","timestamp":1478011403000},"page":"272-282","source":"Crossref","is-referenced-by-count":49,"title":["RETRACTED: Inhibition of the SphK1\/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells"],"prefix":"10.1002","volume":"43","author":[{"given":"B\u00e1rbara","family":"Gonz\u00e1lez\u2010Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Institute of Biomedicine (IBIOMED), University of Le\u00f3n Le\u00f3n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana I.","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine (IBIOMED), University of Le\u00f3n Le\u00f3n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Crespo","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine (IBIOMED), University of Le\u00f3n Le\u00f3n Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Le\u00f3n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"San\u2010Miguel","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine (IBIOMED), University of Le\u00f3n Le\u00f3n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelino","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Department of Animal Health University of Le\u00f3n Le\u00f3n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda J.","family":"Tu\u00f1\u00f3n","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine (IBIOMED), University of Le\u00f3n Le\u00f3n Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Le\u00f3n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Gonz\u00e1lez\u2010Gallego","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine (IBIOMED), University of Le\u00f3n Le\u00f3n Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Le\u00f3n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2010.08.001"},{"key":"e_1_2_7_3_1","first-page":"14839","article-title":"Intracellular sphingosine 1\u2010phosphate contributes to collagen expression of hepatic myofibroblasts in human liver fibrosis independent of its receptors","volume":"288","author":"Xiu L.","year":"2015","journal-title":"J. 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