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The therapeutic applicability of palbociclib, a cyclin\u2010dependent kinase 4 and 6 (CDK4\/6) inhibitor clinically used to treat cancer, in the treatment of neutrophil\u2010associated psoriasis remains undefined. In this study, we evaluated the therapeutic potential and pharmacological effect of palbociclib on neutrophil\u2010associated psoriasiform dermatitis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>The anti\u2010inflammatory effects of palbociclib were determined in activated human neutrophils. The therapeutic feasibility of palbociclib in psoriasis was demonstrated in a mouse model of imiquimod\u2010induced psoriasiform dermatitis. The in vitro enzymatic assays and in silico analyses were used to identify the underlying pharmacological mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>This study found that palbociclib inhibited neutrophilic inflammation, including superoxide anion generation, reactive oxygen species (ROS) formation, elastase degranulation and chemotactic responses. The mechanistic studies identified that the anti\u2010inflammatory effects of palbociclib involved the targeting of phosphatidylinositol 3\u2010kinase (PI3K) but not CDK4\/6 in human neutrophils. Palbociclib preferentially targeted the p110\u03b4 catalytic subunit of PI3K and thereby blocked signalling via the PI3K\/protein kinase B (Akt) pathway. Furthermore, topical application of palbociclib significantly ameliorated imiquimod\u2010induced psoriasiform dermatitis in mice, including psoriatic symptoms, neutrophil infiltration, Akt activation and cytokine up\u2010regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>This is the first study to demonstrate that palbociclib can potentially be used to treat neutrophil\u2010associated psoriasiform dermatitis through the targeting of neutrophilic PI3K activity. Our findings prompt further research to explore the potential of palbociclib and PI3K in psoriasis and other inflammatory diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16080","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T02:22:37Z","timestamp":1679883757000},"page":"2172-2188","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Palbociclib blocks neutrophilic phosphatidylinositol 3\u2010kinase activity to alleviate psoriasiform dermatitis"],"prefix":"10.1111","volume":"180","author":[{"given":"Po\u2010Jen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Medical Research E\u2010DA Hospital, I\u2010Shou University  Kaohsiung 824410 Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin\u2010Hui","family":"Tseng","sequence":"additional","affiliation":[{"name":"Graduate Institute of Natural Products, School 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