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Neuraminidase 4 (NEU4), an enzyme that removes sialic acids from glycoconjugates, has an unclear role in chronic progressive fibrosis. Here, this study finds that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation is observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial\u2010to\u2010mesenchymal transition, reduces the production of pro\u2010fibrotic cytokines, and decreases cellular senescence in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4<jats:sub>254\u2010388aa<\/jats:sub> interacts with Yes\u2010associated protein (YAP) at WW2 domain (231\u2010263aa), promoting its nucleus translocation and activation of target genes, thereby contributing to renal fibrosis. 3,5,6,7,8,3\u02b9,4\u02b9\u2010Heptamethoxyflavone, a natural compound, is identified as a novel NEU4 inhibitor, effectively protecting mice from renal fibrosis in a NEU4\u2010dependent manner. Collectively, the findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis.<\/jats:p>","DOI":"10.1002\/advs.202406936","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T04:59:35Z","timestamp":1723525175000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Targeting Neuraminidase 4 Attenuates Kidney Fibrosis in Mice"],"prefix":"10.1002","volume":"11","author":[{"given":"Ping\u2010Ting","family":"Xiao","sequence":"first","affiliation":[{"name":"School of Pharmacy Nanjing University of Chinese Medicine  Nanjing 210023 China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing 210009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010Hua","family":"Hao","sequence":"additional","affiliation":[{"name":"School of Pharmacy Nanjing University of Chinese Medicine  Nanjing 210023 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