ArticleFrontiers in pharmacology2026
FGFR1/YAP1 signaling in endothelial cells drives renal fibrosis and offers a therapeutic target.
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Abstract
Renal fibrosis is the common pathological pathway for all chronic kidney diseases (CKD) progressing to end-stage renal failure, yet no current therapies can directly halt or reverse this process. Yes-associated protein 1 (YAP1), a core effector of the Hippo pathway, is an established driver of fibrosis, yet it presents a formidable challenge for direct pharmacological inhibition due to its structural and functional properties. This study aims to investigate the role of fibroblast growth factor receptor 1 (FGFR1) as an upstream regulator of YAP1 in renal fibrosis and to evaluate the therapeutic potential of targeting this signaling axis. We analyzed human fibrotic kidney samples, a unilateral ureteral obstruction (UUO) mouse model, and in vitro human umbilical vein endothelial cells (HUVECs), combined with genetic, pharmacological, and biochemical techniques, including endothelial-specific gene knockout, inhibitor assays, immunofluorescence, Western blot, and quantitative real-time PCR (qPCR). We found that FGFR1 and YAP1 were coordinately upregulated in the endothelial cells of fibrotic kidneys. Mechanistically, transforming growth factor-β (TGF-β) activated the FGFR1-ERK-YAP1 signaling cascade, which drove endothelial-to-mesenchymal transition (EndMT), inflammatory responses, and endothelial dysfunction. In vitro, both pharmacological inhibition of FGFR1 with PD173074 and genetic knockdown of FGFR1 or YAP1 effectively blocked this pro-fibrotic cascade. Consistent with in vitro findings, in the UUO mouse model, endothelial-specific deletion of YAP1 or administration of PD173074 significantly attenuated renal fibrosis, inflammatory responses, and vascular dysfunction, while preserving renal function. In addition, the pro-fibrotic function of this axis was further validated in a diabetic kidney disease mouse model. In conclusion, this study identifies the endothelial FGFR1/YAP1 axis as one of the important pro-fibrotic drivers in renal fibrosis progression and proposes an innovative therapeutic concept: indirectly modulating the "undruggable" transcriptional co-activator YAP1 by targeting its upstream, pharmacologically tractable receptor FGFR1. This strategy provides a novel interventional approach and potential target for anti-fibrotic intervention in CKD.
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