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However, the isoform\u2010specific roles of Gli transcription factors remain unclear. This study aimed to elucidate the contribution of Gli2 to renal fibrosis. Multiple murine models of renal fibrosis\u2014unilateral ureteral obstruction, ischemia\u2013reperfusion injury, and aristolochic acid nephropathy\u2014were employed, alongside human CKD specimens. In\u00a0vitro assays, including genetic silencing, overexpression, co\u2010immunoprecipitation, immunofluorescence, promoter analysis, F\u2010actin staining, and TGF\u2010\u03b2\/SB431542 intervention assays were used to evaluate Gli2 function and its interaction with FoxM1. This study identifies Gli2, but not Gli1 or Gli3, as the primary Hedgehog signaling mediator in fibrotic kidneys, showing its activation in both epithelial and interstitial compartments. TGF\u2010\u03b2\u2010induced Gli2 activation promoted fibrogenesis via tubular epithelial\u2010mesenchymal transition (EMT) and fibroblast\u2010to\u2010myofibroblast differentiation (FMD), and cytoskeletal remodeling. FoxM1 is a potential dowgnstream candidate transcriptionally regulated by Gli2, with two conserved Gli\u2010binding sites within its promoter. FoxM1 knockdown partially mitigated Gli2\u2010driven fibrotic effects. Pharmacological Gli2 suppression with GANT61 alleviated fibrotic injury in the UUO mouse model. In conclusion, activated Gli2 is closely associated with renal tubulointerstitial fibrosis and may facilitate fibrogenesis in a FoxM1\u2010relevant regulatory pattern. The TGF\u2010\u03b2\/Hedgehog\/Gli2\/FoxM1 axis represents a promising therapeutic target for combating progressive CKD.<\/jats:p>","DOI":"10.1096\/fj.202505076rr","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T14:10:38Z","timestamp":1781532638000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epithelial and Interstitial Gli2 Activation Correlates With Renal Tubulointerstitial Fibrosis and Facilitates FoxM1\u2010Associated Myofibroblast Phenotypic Transition"],"prefix":"10.1096","volume":"40","author":[{"given":"Ziwei","family":"Yuan","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Clinical Nutrition and Intervention, First Affiliated Hospital Wenzhou Medical University  Wenzhou China"},{"name":"Department of Laboratory Medicine The Third People's Hospital of Ganzhou  Ganzhou 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