NR5A2 promotes epithelial-to-mesenchymal transition in renal fibrosis by targeting MMP25 transcription

Renal fibrosis is a hallmark of chronic kidney disease (CKD), with epithelial-mesenchymal transition (EMT) recognized as a key contributing process. Here, we identify nuclear receptor NR5A2 as an important regulator that promotes EMT in renal tubular epithelial cells through transcriptional activation of MMP25. NR5A2 expression was consistently elevated in human fibrotic kidneys, a unilateral ureteral obstruction (UUO) mouse model, and TGF-β1-treated HK-2 cells. Both siRNA-mediated knockdown and pharmacological inhibition with ML-180 attenuated EMT markers and fibrotic responses. Mechanistically, NR5A2 directly bound to the MMP25 promoter, as demonstrated by luciferase reporter assays, ChIP-qPCR, and molecular docking analysis, while MMP25 silencing counteracted NR5A2-driven EMT. These findings suggest that the NR5A2-MMP25 axis contributes to renal fibrogenesis and may represent a potential therapeutic target for CKD.