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While estrogens are known to modulate immune responses, the role of the G protein-coupled estrogen receptor 1 (GPER1) in skin inflammation remains poorly understood. Here, we show that GPER1 signaling is downregulated in lesional skin of psoriasis patients and negatively correlates with both inflammation markers and KC proliferation. Using a zebrafish model of chronic skin inflammation (Spint1a-deficient larvae), we demonstrate that Gper1 deficiency leads to increased KC proliferation and enhanced neutrophil infiltration, without directly modulating inflammatory signaling. Pharmacological inhibition of cell proliferation with palbociclib reduced both KC aggregates and neutrophil infiltration, independently of NF-\u03baB activation. Moreover, Gper1 overexpression in basal KCs, but not in neutrophils, rescued skin alterations, indicating a cell-autonomous effect in KCs. Notably, our results also suggest that epithelial cell proliferation facilitates immune cell infiltration into inflamed tissue. Together, our results identify GPER1 as a negative regulator of keratinocyte hyperproliferation and skin inflammation, suggesting that modulation of this pathway may represent a therapeutic strategy for hyperproliferative inflammatory skin diseases such as psoriasis.<\/jats:p>","DOI":"10.1038\/s41420-026-03059-1","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T23:28:43Z","timestamp":1774049323000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["GPER1 reduces skin inflammation by inhibiting keratinocyte proliferation"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1072-5902","authenticated-orcid":false,"given":"Natalia","family":"P\u00e9rez-Escudero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9627-051X","authenticated-orcid":false,"given":"Isabel","family":"Cabas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal","family":"Corbal\u00e1n-V\u00e9lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Mart\u00ednez-Mench\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"Ferri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda L.","family":"Cayuela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1521-2327","authenticated-orcid":false,"given":"Diana","family":"Garc\u00eda-Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6860-2153","authenticated-orcid":false,"given":"Alfonsa","family":"Garc\u00eda-Ayala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9527-0211","authenticated-orcid":false,"given":"Victoriano","family":"Mulero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"3059_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.880201","volume":"13","author":"J Bu","year":"2022","unstructured":"Bu J, Ding R, Zhou L, Chen X, Shen E. 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Experiments and procedures were performed as approved by the Bioethical Committees of the University of Murcia (approval number #669\/2020). Samples from patients included in this study were collected, processed, and provided by the Biobanco en Red de la Regi\u00f3n de Murcia, BIOBANC-MUR, registered with registration number B.0000859, and were processed following standard operating procedures, including informed consent from all participants, with appropriate approval from the CEIm (approval numbers #8\/13 and #6\/2017).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"166"}}