The family of HIF-PH (HIF prolyl hydroxylase) enzymes are the main molecular to regulate HIF activity through hydroxylation at 2 proline residues and cause the degradation of HIF, thus leading to inhibition on accumulation of functional HIF under normoxia. Roxadustat (FG-4592) is the second generation HIF-PH inhibitor. Treatment with FG-4592 on dose of 5 - 50 μM can stabilize HIF-1α and inhibit apoptosis in tert-Butylhydroperoxide-stimulated PC12 cells. Intraperitoneal injection with FG-4592, 50 mg/kg/day, showed neuroprotection against spinal cord injury through stabilization of HIF-1α in SCI (Traumatic spinal cord injury) mice model[1]. FG-4592 (50 μM) can increase HiPO4-induced mineralization through up-regulation of HIF-1α levels in vascular smooth muscle cells[2]. For Roxadustat can induce elevations in endogenous EPO levels and hemoglobin levels, it is now used to treatment of anemia in chronic kidney disease[3].
作用机制
Most HIF-PH inhibitors are 2-oxogluarate derivatives, region of which can compete with HIF[4].
Roxadustat/罗沙司他 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Primary human myotubes
10 μmol/l
24 hours
To evaluate the effect of Roxadustat on glucose metabolism, results showed that Roxadustat increased glycolytic rate and inhibited mitochondrial respiration
Diabetologia. 2024 Sep;67(9):1943-1954
Caco-2 cells
20, 50, 100 μM
1, 3, 6, 24 hours
To evaluate the regulatory effect of FG-4592 on FPN expression, results showed that FG-4592 significantly upregulated FPN mRNA and protein levels and promoted FPN transcription through HIF2α binding to HREs on the FPN promoter.
Adv Sci (Weinh). 2024 Mar;11(12):e2307022
UMR-106 cells
50 μM
24 hours
To investigate the effect of FG-4592 on iFGF23 levels in osteoblast-like cells. Results showed that FG-4592 promoted iFGF23 cleavage by upregulating Furin enzyme expression.
Cell Commun Signal. 2025 Apr 25;23(1):200
HK-2 cells
50 μM
24 hours
To investigate the inhibitory effect of FG-4592 on tubular epithelial cell fibrogenesis. Results showed that FG-4592 significantly downregulated the mRNA expression of Fn1, Acta2, and Col1a1.
Cell Commun Signal. 2025 Apr 25;23(1):200
Roxadustat/罗沙司他 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Tmprss6 knockout mice, anemia of chronic kidney disease (CKD) model, anemia of inflammation (AI) model, 5-fluorouracil-induced chemotherapy-related anemia (CRA) model
Oral gavage
30 mg/kg
Once daily for 4 weeks
To evaluate the therapeutic effect of FG-4592 on various anemia models, results showed that FG-4592 promoted iron absorption and ameliorated anemia symptoms by stabilizing duodenal Hif2α and upregulating Fpn expression, independent of hepatic Hamp expression.
Adv Sci (Weinh). 2024 Mar;11(12):e2307022
Sprague-Dawley rats
Chronic kidney disease (CKD) model
Oral gavage
20 mg/kg
Three times a week for 12 weeks
To evaluate the effect of FG-4592 on renal fibrosis in CKD rats. Results showed that FG-4592 significantly improved renal function and attenuated tubulointerstitial fibrosis.
搜索
