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Here, we establish a genetically defined, multi\u2010hit mouse model that recapitulates the sustained hyperuricemia, metabolic dysregulation, and progressive fibrosis of human disease. Using this model, we demonstrate that soluble uric acid activates the renal NLRP3 inflammasome and that its inhibition attenuates kidney injury. Single\u2010nucleus RNA sequencing revealed a distinct pro\u2010inflammatory and pro\u2010fibrotic proximal tubule cell population (Profib PT) marked by high VCAM1 expression, which is conserved in human kidney disease. Direct VCAM1 neutralization with antibodies attenuated renal fibrosis, validating its functional role. Mechanistically, we identify glutathione peroxidase 3 (GPX3) as a master regulator restraining precursor cell differentiation into Profib PT cells. GPX3 expression is suppressed in hyperuricemia, licensing this pathogenic transition; conversely, dietary selenium supplementation restored GPX3 activity, blocked Profib PT differentiation and VCAM1\u2010dependent macrophage adhesion, and ameliorated renal fibrosis. Our findings define the GPX3\u2010VCAM1 axis as a central regulatory node in hyperuricemic nephropathy and identify nutritional selenium repletion as a novel therapeutic strategy to intercept fibrosis.<\/jats:p>","DOI":"10.1002\/advs.77676","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:46:30Z","timestamp":1789019190000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The GPX3\u2010VCAM1 Axis Gates Pro\u2010Fibrotic Tubule Cell Fate in Hyperuricemic Nephropathy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1380-9365","authenticated-orcid":false,"given":"Yunfei","family":"Qi","sequence":"first","affiliation":[{"name":"Shanghai Institute of Nutrition and Health Chinese Academy of Sciences University of Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health Chinese Academy of Sciences University of Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7395-1505","authenticated-orcid":false,"given":"Yue","family":"Lve","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health Chinese Academy of Sciences University of Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaming","family":"Yuan","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health Chinese Academy of Sciences University of Chinese Academy of Sciences  Shanghai 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 Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health Chinese Academy of Sciences University of Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health Chinese Academy of Sciences University of Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunping","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Transplantation Surgery Department of General Surgery, Nanjing Drum Tower Hospital the Affiliated Hospital of Medical School Nanjing University  Nanjing China"},{"name":"Jinan Microecological Biomedicine Shandong Laboratory  Jinan China"},{"name":"Department of Hepatobiliary and Pancreatic Surgery The Second Affiliated Hospital of Fujian Medical University  Quanzhou China"},{"name":"Renhuai People's Hospital  Renhuai Guizhou Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9906-6787","authenticated-orcid":false,"given":"Qiurong","family":"Ding","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health Chinese Academy of Sciences University of Chinese Academy of Sciences  Shanghai China"},{"name":"Shanghai Key Laboratory of Reproductive Medicine  Shanghai China"},{"name":"Hubei Key Laboratory of Selenium Resource Research and Biological Application Hubei Minzu University  Enshi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102369\u201012\u201036"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.121061"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gft029"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000326848"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc10\u20100227"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2015.06.015"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102369\u201015\u2010122"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2007.05.013"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2024.10.022"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00272.2019"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04516"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2020.05.056"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep39884"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2015.03.250"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis\u20102014\u2010206564"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.09.013"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926\u2010011\u20100162\u20101"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2018.01.006"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523\u20101755.2005.00273.x"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000345509"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005050572"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.3904\/kjim.2020.340"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201062599\u20109"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ado2849"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2005477117"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590\u2010022\u201001200\u20107"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584\u2010019\u20100222\u2010x"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214\u2010109X(24)00012\u20103"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41733"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.42009"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41522\u2010021\u201000235\u20102"},{"key":"e_1_2_12_33_1","doi-asserted-by":"crossref","unstructured":"Y.\u2010X.Xu 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