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This study explored the role of Hepatocyte Nuclear Factor 3 alpha (HNF3\u03b1\/FOXA1) in renal fibrosis and CKD after IRI. Kidney biopsy specimens from CKD patients and mouse models (IRI or unilateral ureteral obstruction) showed HNF3\u03b1 upregulation in fibrotic kidneys, linked to renal function decline. Additional experiments demonstrated that deletion of HNF3\u03b1 mitigated IRI\u2010induced renal fibrosis, and that overexpression of HNF3\u03b1 led to increased fibrosis. Examination of the potential mechanism by transcriptome sequencing and CUT&amp;Tag sequencing suggested that HNF3\u03b1 promoted renal fibrosis by increasing the expression of the NCK associated protein 1 like (Nckap1l, formerly known as hematopoietic protein 1 [Hem1]), a vital component of the WAVE complex which plays a significant role in cytoskeletal regulation and cell migration. 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