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The aim of this study was to characterize VCE\u2010004.3, a novel cannabidiol derivative, and study its anti\u2010inflammatory and anti\u2010fibrotic activities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      The binding of VCE\u2010004.3 to CB\n                      <jats:sub>1<\/jats:sub>\n                      and CB\n                      <jats:sub>2<\/jats:sub>\n                      receptors and PPAR\u03b3 and its effect on their functional activities were studied\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in silico<\/jats:italic>\n                      . Anti\u2010fibrotic effects of VCE\u2010004.3 were investigated in NIH\u20103T3 fibroblasts and human dermal fibroblasts. To assess its anti\u2010inflammatory and anti\u2010fibrotic efficacy\n                      <jats:italic>in vivo<\/jats:italic>\n                      , we used two complementary models of bleomycin\u2010induced fibrosis. Its effect on ERK1\/2 phosphorylation induced by IgG from SSc patients and PDGF was also investigated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      VCE\u2010004.3 bound to and activated PPAR\u03b3 and CB\n                      <jats:sub>2<\/jats:sub>\n                      receptors and antagonized CB\n                      <jats:sub>1<\/jats:sub>\n                      receptors. VCE\u2010004.3 bound to an alternative site at the PPAR\u03b3 ligand binding pocket. VCE\u2010004.3 inhibited collagen gene transcription and synthesis and prevented TGF\u03b2\u2010induced fibroblast migration and differentiation to myofibroblasts. It prevented skin fibrosis, myofibroblast differentiation and ERK1\/2 phosphorylation in bleomycin\u2010induced skin fibrosis. Furthermore, it reduced mast cell degranulation, macrophage activation, T\u2010lymphocyte infiltration, and the expression of inflammatory and profibrotic factors. Topical application of VCE\u2010004.3 also alleviated skin fibrosis. Finally, VCE\u2010004.3 inhibited PDGF\u2010BB\u2010 and SSc IgG\u2010induced ERK1\/2 activation in fibroblasts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      VCE\u2010004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPAR\u03b3\/CB\n                      <jats:sub>2<\/jats:sub>\n                      agonist and CB\n                      <jats:sub>1<\/jats:sub>\n                      receptor modulator that could be considered for the development of novel therapies against different forms of scleroderma.\n                    <\/jats:p>\n                  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