The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavage
Abstract Background Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) represents a novel therapeutic approach for renal anemia, a prevalent complication of chronic kidney disease (CKD). However, the effects of HIF-PHI on renal functional outcomes remain poorly characterized. Here, the...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-025-02175-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850172477957734400 |
|---|---|
| author | Jing Wang Zuo-Lin Li Yan Zhou Zhong-Tang Li Yan Tu Xin-Hui Hu Jin-Hua Zhu Bi-Cheng Liu Hong Liu |
| author_facet | Jing Wang Zuo-Lin Li Yan Zhou Zhong-Tang Li Yan Tu Xin-Hui Hu Jin-Hua Zhu Bi-Cheng Liu Hong Liu |
| author_sort | Jing Wang |
| collection | DOAJ |
| description | Abstract Background Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) represents a novel therapeutic approach for renal anemia, a prevalent complication of chronic kidney disease (CKD). 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. Methods 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. Results 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. Conclusions 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. |
| format | Article |
| id | doaj-art-ba9dda9bc41e40c7a42589cc5c661cbc |
| institution | OA Journals |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-ba9dda9bc41e40c7a42589cc5c661cbc2025-08-20T02:20:05ZengBMCCell Communication and Signaling1478-811X2025-04-0123111710.1186/s12964-025-02175-2The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavageJing Wang0Zuo-Lin Li1Yan Zhou2Zhong-Tang Li3Yan Tu4Xin-Hui Hu5Jin-Hua Zhu6Bi-Cheng Liu7Hong Liu8Institute of Nephrology, Zhong da Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhong da Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhong da Hospital, Southeast University School of MedicineDepartment of Paediatrics, Zhong da Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhong da Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhong da Hospital, Southeast University School of MedicineDepartment of Nephrology, People’s Hospital of Yangzhong CityInstitute of Nephrology, Zhong da Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhong da Hospital, Southeast University School of MedicineAbstract Background Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) represents a novel therapeutic approach for renal anemia, a prevalent complication of chronic kidney disease (CKD). 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. Methods 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. Results 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. Conclusions 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.https://doi.org/10.1186/s12964-025-02175-2RoxadustatTubulointerstitial fibrosisFGF23AnemiaFurin |
| spellingShingle | Jing Wang Zuo-Lin Li Yan Zhou Zhong-Tang Li Yan Tu Xin-Hui Hu Jin-Hua Zhu Bi-Cheng Liu Hong Liu The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavage Cell Communication and Signaling Roxadustat Tubulointerstitial fibrosis FGF23 Anemia Furin |
| title | The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavage |
| title_full | The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavage |
| title_fullStr | The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavage |
| title_full_unstemmed | The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavage |
| title_short | The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavage |
| title_sort | roxadustat fg 4592 ameliorates tubulointerstitial fibrosis by promoting intact fgf23 cleavage |
| topic | Roxadustat Tubulointerstitial fibrosis FGF23 Anemia Furin |
| url | https://doi.org/10.1186/s12964-025-02175-2 |
| work_keys_str_mv | AT jingwang theroxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT zuolinli theroxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT yanzhou theroxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT zhongtangli theroxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT yantu theroxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT xinhuihu theroxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT jinhuazhu theroxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT bichengliu theroxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT hongliu theroxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT jingwang roxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT zuolinli roxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT yanzhou roxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT zhongtangli roxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT yantu roxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT xinhuihu roxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT jinhuazhu roxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT bichengliu roxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage AT hongliu roxadustatfg4592amelioratestubulointerstitialfibrosisbypromotingintactfgf23cleavage |