{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:10:41Z","timestamp":1788844241539,"version":"build-2803163510"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Keloids are fibroproliferative disorders conditions of the dermis with dysregulated immune responses contributing to disease progression. However, the causal inflammatory mediators and their pathogenic mechanisms remain undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>This study aims to identify causal inflammatory mediators for keloids and their pathogenic mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>Two\u2013sample Mendelian randomization (MR) analyses were performed using genetic instruments for 91 inflammatory proteins as exposures and genome\u2013wide association study (GWAS) summary statistics for keloid susceptibility as the outcome. Sensitivity analyses were conducted to assess the robustness of MR findings. Single\u2013cell RNA sequencing (scRNA\u2013seq) datasets from keloid tissues were analyzed to identify the cellular distribution of prioritized candidates. Functional validation was performed using immunohistochemistry (IHC), immunofluorescence staining, qRT\u2013PCR, western blotting, siRNA\u2013mediated knockdown, recombinant protein stimulation, and transcriptome sequencing. Pharmacological inhibition and rescue experiments were further performed to investigate the downstream signaling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MR analysis identified five inflammatory proteins with potential causal associations with keloid susceptibility, among which urokinase\u2013type plasminogen activator (PLAU) was the only one consistently enriched in fibroblasts across two independent scRNA\u2013seq datasets. PLAU expression was significantly elevated at both the mRNA and protein levels in keloid tissues and primary fibroblasts. PLAU knockdown in keloid fibroblasts reduced collagen I\/III expression, proliferation, and migration, whereas recombinant PLAU stimulation enhanced these profibrotic phenotypes in normal dermal fibroblasts. Mechanistically, RNA\u2013sequencing implicated activation of the TGF\u2013\u03b2 signaling pathway. Furthermore, inhibition of TGF\u2013\u03b2 receptor signaling attenuated PLAU\u2013induced profibrotic responses, while exogenous TGF\u2013\u03b21 rescued the effects of PLAU depletion. Importantly, PLAUR knockdown attenuated PLAU\u2013induced TGF\u2013\u03b2\/Smad activation and reduced PLAU\u2013mediated enhancement of fibroblast activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This integrative study identifies PLAU as a genetically supported and biologically relevant mediator of keloid fibrosis. PLAU promotes fibroblast activation through PLAUR\u2013dependent regulation of the TGF\u2013\u03b2\/Smad signaling pathway, leading to enhanced collagen production, proliferation, and migration. These findings provide new insights into inflammatory regulation in keloid pathogenesis and highlight PLAU as a potential therapeutic target for keloid intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1855430","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T04:26:49Z","timestamp":1788841609000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["PLAU promotes fibroblast activation and keloid fibrogenesis through PLAUR\u2013Dependent TGF\u2013\u03b2\/Smad signaling"],"prefix":"10.3389","volume":"17","author":[{"given":"Qing","family":"An","sequence":"first","affiliation":[{"name":"Department of Dermatology and Rheumatology Immunology, Xinqiao Hospital of Army Medical University","place":["Chongqing, China"]},{"name":"Dermatology Hospital, Southern Medical University","place":["Guangzhou, 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