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However, the effects of HIF-PHI on renal functional outcomes remain poorly characterized. Here, the potential effects of FG-4592, an orally administered HIF-PHI, on renal fibrosis were explored systematically.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>In this study, a CKD rat model was established through subtotal 5\/6 nephrectomy. Rats were administered either FG-4592 or vehicle control via oral gavage three times weekly for 12 consecutive weeks. Additionally, recombinant FGF23 was continuously delivered via subcutaneously implanted Alzet osmotic minipumps for 28 days.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Interestingly, we found that CKD-induced anemia was significantly ameliorated in CKD rats with FG-4592 treatment. Meanwhile, markedly alleviated histopathological changes and renal tubulointerstitial fibrosis (TIF) were observed in rats with FG-4592 administration. Notably, serum levels of intact FGF23 (iFGF23) were significantly reduced following FG-4592 administration in CKD rats. This finding was subsequently validated in CKD patients receiving Roxadustat therapy. Mechanistically, we illustrated that inhibition of the iFGF23-WNT5A pathway was the exact mechanism by which FG-4592 ameliorated TIF. Further, we also demonstrated that transcriptional activation of Furin enzyme was the exact molecular mechanism for FG-4592-mediated iFGF23 cleavage.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>FG-4592 attenuates TIF through Furin-mediated proteolytic cleavage of iFGF23. These findings provide novel mechanistic insights into HIF-PHI-mediated renal protection and establish a theoretical framework for clinical translation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12964-025-02175-2","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T19:27:55Z","timestamp":1745609275000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavage"],"prefix":"10.1186","volume":"23","author":[{"given":"Jing","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuo-Lin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong-Tang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Hui","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Hua","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi-Cheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"2175_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2022.100438","volume":"20","author":"J Sundstr\u00f6m","year":"2022","unstructured":"Sundstr\u00f6m J, Bodegard J, Bollmann A, et al. 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