{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T19:30:01Z","timestamp":1793388601852,"version":"4.5.0"},"reference-count":144,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T00:00:00Z","timestamp":1674000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006952","name":"Louisiana Board of Regents","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006952","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to aberrant cytokine production, psoriasis is associated with activation of the Akt\/mTOR pathway. mTOR\/S6K1 regulates T-lymphocyte activation and migration, keratinocytes proliferation and is upregulated in psoriatic lesions. Several drugs that target Th1\/Th17 cytokines or their receptors have been approved for treating psoriasis in humans with variable results necessitating improved therapies. Fisetin, a natural dietary polyphenol with anti-oxidant and anti-proliferative properties, covalently binds mTOR\/S6K1. The effects of fisetin on psoriasis and its underlying mechanisms have not been clearly defined. Here, we evaluated the immunomodulatory effects of fisetin on Th1\/Th17-cytokine-activated adult human epidermal keratinocytes (HEKa) and anti-CD3\/CD28-stimulated inflammatory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and compared these activities with those of rapamycin (an mTOR inhibitor). Transcriptomic analysis of HEKa revealed 12,713 differentially expressed genes (DEGs) in the fisetin-treated group compared to 7,374 DEGs in the rapamycin-treated group, both individually compared to a cytokine treated group. Gene ontology analysis revealed enriched functional groups related to PI3K\/Akt\/mTOR signaling pathways, psoriasis, and epidermal development. Using\n                    <jats:italic>in silico<\/jats:italic>\n                    molecular modeling, we observed a high binding affinity of fisetin to IL-17A.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , fisetin significantly inhibited mTOR activity, increased the expression of autophagy markers LC3A\/B and Atg5 in HEKa cells and suppressed the secretion of IL-17A by activated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T lymphocytes or T lymphocytes co-cultured with HEKa. Topical administration of fisetin in an imiquimod (IMQ)-induced mouse psoriasis model exhibited a better effect than rapamycin in reducing psoriasis-like inflammation and Akt\/mTOR phosphorylation and promoting keratinocyte differentiation and autophagy in mice skin lesions. Fisetin also significantly inhibited T-lymphocytes and F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    macrophage infiltration into skin. We conclude that fisetin potently inhibits IL-17A and the Akt\/mTOR pathway and promotes keratinocyte differentiation and autophagy to alleviate IMQ-induced psoriasis-like disease in mice. Altogether, our findings suggest fisetin as a potential treatment for psoriasis and possibly other inflammatory skin diseases.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.1075804","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T02:03:14Z","timestamp":1674007394000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":57,"title":["Dual targeting of mTOR\/IL-17A and autophagy by fisetin alleviates psoriasis-like skin inflammation"],"prefix":"10.3389","volume":"13","author":[{"given":"Tithi","family":"Roy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergette","family":"Banang-Mbeumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel T.","family":"Boateng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle 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