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Gasdermin D (GSDMD)\u2010mediated pyroptosis amplifies the inflammatory and fibrogenic cascade, yet its role in chronic kidney disease (CKD) remains elusive. Herein, GSDMD is upregulated in kidney macrophages following unilateral renal ischemia\u2010reperfusion injury (UIRI) or folic acid\u2010induced injury, paralleling elevated pyroptosis rates. Clinically, the active fragment GSDMD\u2010N localizes primarily to CD68\u207a macrophages, and its renal level positively correlates with fibrosis severity across diverse CKD etiologies, reinforcing its pathogenic relevance. Macrophage\u2010specific deletion of\n                    <jats:italic>Gsdmd<\/jats:italic>\n                    ameliorates pyroptosis, inflammation, and renal fibrosis in both murine models, without affecting acute tubular damage in bilateral IRI. Mechanistically, injured TECs initiate this cascade through secreted IFN\u2010\u03b1, which activates the IFNAR1\/JAK2\/STAT2 axis in macrophages\u200b. STAT2 then forms a complex with IRF9, directly binding to the\n                    <jats:italic>Gsdmd<\/jats:italic>\n                    promoter to transcriptionally upregulate GSDMD expression. Genetic ablation of\n                    <jats:italic>Jak2<\/jats:italic>\n                    ,\n                    <jats:italic>Stat2<\/jats:italic>\n                    , or\n                    <jats:italic>Ifnar1<\/jats:italic>\n                    reduces GSDMD and GSDMD\u2010N levels and inhibits IL\u20101\u03b2\/IL\u201018 secretion. Notably, administration of an IFN\u2010\u03b1 neutralizing antibody attenuates UIRI\u2010induced pyroptotic macrophage, inflammation, and renal fibrosis. Collectively, the findings uncover a STAT2\/IRF9\u2010dependent paracrine IFN\u2010\u03b1 feedback loop that orchestrates GSDMD\u2010mediated pyroptosis, linking injured TECs to macrophage\u2010driven renal inflammation and fibrosis. Targeting this axis represents a promising strategy to halt CKD progression.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512278","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T01:56:38Z","timestamp":1765590998000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tubule\u2010Derived IFN\u2010\u03b1 Promotes GSDMD\u2010Mediated Macrophage Pyroptosis to Drive Renal Inflammation and Fibrosis Through JAK2\/STAT2 Activation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7517-5137","authenticated-orcid":false,"given":"Yiping","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Nephrology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou 510080 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Wang","sequence":"additional","affiliation":[{"name":"Department 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