{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:03:02Z","timestamp":1790971382732,"version":"4.1.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018925","name":"Health Commission of Henan Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011447","name":"Science and Technology Department of Henan Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011447","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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-\u03b2 (TGF-\u03b2) 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 \u201cundruggable\u201d 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.<\/jats:p>","DOI":"10.3389\/fphar.2026.1766265","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T05:44:11Z","timestamp":1776059051000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["FGFR1\/YAP1 signaling in endothelial cells drives renal fibrosis and offers a therapeutic target"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Nephrology, Zhengzhou University People\u2019s Hospital, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafeng","family":"Ren","sequence":"additional","affiliation":[{"name":"Henan Provincial Key Laboratory of Kidney Disease Innovation and Translation, Henan International Joint Laboratory of Kidney Disease and Microenvironment, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengli","family":"Yan","sequence":"additional","affiliation":[{"name":"Henan Provincial Key Laboratory of Kidney Disease Innovation and Translation, Henan International Joint Laboratory of Kidney Disease and Microenvironment, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Xinxiang Medical University, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixia","family":"Cao","sequence":"additional","affiliation":[{"name":"Henan Provincial Key Laboratory of Kidney Disease Innovation and Translation, Henan International Joint Laboratory of Kidney Disease and Microenvironment, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengmin","family":"Shao","sequence":"additional","affiliation":[{"name":"Henan Provincial Key Laboratory of Kidney Disease Innovation and Translation, Henan International Joint Laboratory of Kidney Disease and Microenvironment, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1038\/s41581-025-00934-5","article-title":"Advances and challenges in kidney fibrosis therapeutics","volume":"21","author":"Abbad","year":"2025","journal-title":"Nat. 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