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Here, via TGF\u2010\u03b2\u2010treated HK\u20102 cells and an in\u00a0vivo unilateral ureteral obstruction mice model, the histone lysine methyltransferase family was screened and the upregulated expression of KMT5a was identified in these renal fibrosis models. Interference assays using lentivirus transfection in HK\u20102 cells and transgenic mice displayed that KMT5a silencing in HK\u20102 cells impeded macrophage chemotaxis. Moreover, in\u00a0vivo, transgenic KMT5a knockout inhibited macrophage infiltration, which contributed to the suppression of renal fibrosis progression. Mechanistically, by immunoprecipitation assays and mass spectrometry, we discovered that KMT5a could interact with and stabilize the transcription factor IRF3 to regulate macrophage chemotaxis and infiltration in renal tissues, which accelerated renal fibrosis progression. Notably, we confirmed that a small molecular inhibitor of KMT5a, UNC0379, reduced IRF3 protein levels and macrophage chemotaxis, thus suppressing renal fibrosis, in\u00a0vitro and in\u00a0vivo. Therefore, this study presented KMT5a as a mediator of renal fibrosis progression, an effect that was reversed by the KMT5a inhibitor UNC0379, which provided evidence of a novel target and potential drug for inhibiting renal fibrosis progression.<\/jats:p>","DOI":"10.1096\/fj.202601180rr","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T10:30:43Z","timestamp":1784975443000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>KMT5a<\/scp>\n                    \u2010Mediated\n                    <scp>IRF3<\/scp>\n                    Stabilization Enhances Macrophage Chemotaxis and Renal Fibrosis Progression"],"prefix":"10.1096","volume":"40","author":[{"given":"Mingzheng","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Traditional Chinese Medicine The First Affiliated Hospital of Soochow University  Suzhou People's Republic of China"},{"name":"Department 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