{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:26:08Z","timestamp":1789147568188,"version":"build-2803163510"},"reference-count":65,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,2]],"date-time":"2021-10-02T00:00:00Z","timestamp":1633132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009647","name":"Ministry of Health","doi-asserted-by":"publisher","award":["GR-2013-02355700"],"award-info":[{"award-number":["GR-2013-02355700"]}],"id":[{"id":"10.13039\/100009647","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is aberrantly activated in psoriatic lesions and contributes to disease pathogenesis. Among PI3Ks enzymes, PI3K\u03b1, \u03b2, and \u03b4 isoforms are known to bind the p85 regulatory subunit and mediate activation of AKT and other downstream effectors. In this study, we deepened our understanding of the expression and function of PI3K\u03b4 in skin lesions of patients affected by psoriasis. For the first time, we found that PI3K\u03b4 is overexpressed in psoriatic plaques, and its expression is not only confined to infiltrating immune cells but also accumulates in proliferating keratinocytes of the epidermal basal layer. We investigated the function of PI3K\u03b4 in psoriatic skin by evaluating the impact of seletalisib, a newly developed selective PI3K\u03b4 inhibitor, in both in vitro and in vivo experimental models of psoriasis. Of note, we found that PI3K\u03b4 sustains keratinocyte hyperproliferation and impaired terminal differentiation induced by IL-22, as well as induces epithelial inflammation and resistance to apoptosis mediated by TNF-\u03b1 in human keratinocytes. Mechanistically, PI3K\u03b4 promotes PDK1 phosphorylation and signals through AKT-dependent or -independent pathways. It is worth mentioning that PI3K\u03b4 inhibition by seletalisib attenuates the severity of psoriasiform phenotype induced in the Imiquimod-induced mouse model of psoriasis by restoring the physiological proliferation and differentiation programs in epidermal keratinocytes and contrasting the cutaneous inflammatory responses. Therefore, we suggest PI3K\u03b4 as a potential topically druggable target in psoriasis and skin diseases characterized by epidermal hyperproliferation and skin inflammation.<\/jats:p>","DOI":"10.3390\/cells10102636","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T09:24:15Z","timestamp":1633339455000},"page":"2636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["PI3K\u03b4 Sustains Keratinocyte Hyperproliferation and Epithelial Inflammation: Implications for a Topically Druggable Target in Psoriasis"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0629-1729","authenticated-orcid":false,"given":"Laura","family":"Mercurio","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Immunology, Istituto Dermopatico dell\u2019Immacolata IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7299-2393","authenticated-orcid":false,"given":"Martina","family":"Morelli","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, Istituto Dermopatico dell\u2019Immacolata IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2323-8519","authenticated-orcid":false,"given":"Claudia","family":"Scarponi","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, Istituto Dermopatico dell\u2019Immacolata IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Luca","family":"Scaglione","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, Istituto Dermopatico dell\u2019Immacolata IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabatino","family":"Pallotta","sequence":"additional","affiliation":[{"name":"Integrated Center for Research in Psoriasis (CRI-PSO), Istituto Dermopatico dell\u2019Immacolata IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7537-6833","authenticated-orcid":false,"given":"Cristina","family":"Albanesi","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, Istituto Dermopatico dell\u2019Immacolata IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy"},{"name":"Integrated Center for Research in Psoriasis (CRI-PSO), Istituto Dermopatico dell\u2019Immacolata IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0585-6783","authenticated-orcid":false,"given":"Stefania","family":"Madonna","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, Istituto Dermopatico dell\u2019Immacolata IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy"},{"name":"Integrated Center for Research in Psoriasis (CRI-PSO), Istituto Dermopatico dell\u2019Immacolata IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1056\/NEJMra0804595","article-title":"Mechanisms of disease: Psoriasis","volume":"361","author":"Nestle","year":"2009","journal-title":"N. 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