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Last update 08 May 2025

PHD2 x HIF-1α

Last update 08 May 2025

Basic Info

Related Targets

PHD2HIF-1α

Drugs associated with PHD2 x HIF-1α

FG-2216

Target

HIF-1α x PHD2

Mechanism

HIF-1α inhibitors [+1]

Active Org.-

Originator Org.

Astellas Pharma, Inc.

Active Indication-

Inactive Indication

Anemia [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with PHD2 x HIF-1α

NCT00456053

/ CompletedPhase 2

A Randomized Study of the Safety and Efficacy of FG-2216 in Subjects With Renal Anemia Not Requiring Dialysis and Not Receiving Recombinant Human Erythropoietin

The purpose of this study is to test the safety and efficacy of FG-2216 in the treatment of patients with renal anemia who are not receiving erythropoietin and who are not on dialysis.

Start Date01 Dec 2005

Sponsor / Collaborator

FibroGen, Inc.

100 Clinical Results associated with PHD2 x HIF-1α

100 Translational Medicine associated with PHD2 x HIF-1α

0 Patents (Medical) associated with PHD2 x HIF-1α

452

Literatures (Medical) associated with PHD2 x HIF-1α

01 Apr 2025·Redox Biology

Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2

Article

Author: Yegambaram, Manivannan ; Wang, Ting ; Fineman, Jeffrey R ; Garcia Flores, Alejandro E ; Lu, Qing ; Pokharel, Marissa D ; Aggarwal, Saurabh ; Black, Stephen M ; Soto, Jamie ; Sun, Xutong

Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and increases glycolytic ATP production and glycolysis. This is due to mitochondrial reactive oxygen species (mito-ROS)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) signaling, and this is linked to hydrogen peroxide (H₂O₂)-mediated inhibition of prolyl hydroxylase domain-2 (PHD2) due to its cysteine 326 oxidation and dimerization. Furthermore, these findings are validated in PAEC isolated from a lamb model of PH, which are glycolytic (Shunt PAEC), exhibit increases in both H₂O₂ and PHD2 dimer levels. The overexpression of catalase reversed the PHD2 dimerization, decreased HIF-1α levels, and attenuated glycolysis in Shunt PAEC. Our data suggest that reducing PHD2 dimerization could be a potential therapeutic target for PH.

01 Apr 2025·Journal of Thrombosis and Haemostasis

Therapeutic potential of roxadustat in immune thrombocytopenia: a Mendelian randomization analysis

Article

Author: Meng, Jinxi ; Dong, Shuyue ; Cheng, Xiaoling ; Lin, Zheyan ; Chen, Zhenping ; Wang, Zhifa ; Hu, Yu ; Ouyang, Juntao ; Ma, Jingyao ; Wu, Runhui

BACKGROUNDImmune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired megakaryocyte maturation. Hypoxia-inducible factor-1α (HIF-1α), pivotal in the development of megakaryocytes and immune regulation, is downregulated in ITP. Roxadustat, which stabilizes HIF-1α, has emerged as a potential therapeutic drug for ITP that acts by enhancing HIF-1α-mediated megakaryocyte development and modulating immune responses.OBJECTIVESThis study evaluates the safety profile of roxadustat and its therapeutic efficacy for ITP treatment using Mendelian randomization (MR) analysis.METHODSWe used expression quantitative trait loci data for roxadustat's target genes (EGLN1, EGLN2, and EGLN3) and genetic associations with ITP and adverse outcomes from the Open Genome-Wide Association Study project. MR analysis included inverse-variance weighted, MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier methods to evaluate pleiotropy. Heterogeneity was assessed using Cochran's Q statistic and I² measure with sensitivity analyses. A meta-analysis was performed to integrate effect sizes from multiple literature sources.RESULTSMR analysis revealed a significant association between roxadustat and reduced ITP risk (odds ratio, 0.79; 95% CI, 0.66-0.95; P = .01) with no evidence of horizontal pleiotropy. Meta-analysis confirmed the protective effect of roxadustat on ITP. Utilizing the expression quantitative trait loci of roxadustat's target gene EGLN1 as instrumental variables, an MR analysis of 39 potential adverse reactions revealed no significant increase, suggesting a favorable safety profile for roxadustat.CONCLUSIONRoxadustat demonstrates a potential protective effect against ITP without increasing the risk of adverse outcomes, suggesting its promise as a therapeutic option for ITP and warranting further investigation.

01 Mar 2025·Free Radical Biology and Medicine

Sulfur dioxide controls M1 macrophage polarization by sulphenylation of prolyl hydroxylase 2 at cysteine 260

Article

Author: Zhang, Han ; Lv, Boyang ; Liu, Keyu ; Huang, Yaqian ; Jin, Hongfang ; Du, Junbao

M1 macrophage polarization plays a pivotal role in inflammation-related diseases. However, the endogenous regulatory factors and mechanisms underlying M1 macrophage polarization have not been entirely clarified. This study aimed to explore whether endogenous sulfur dioxide (SO₂) is involved in M1 macrophage polarization and its mechanism. In the study, we found that the endogenous SO₂/aspartate aminotransferase1 (AAT1) pathway was downregulated during M1 polarization of macrophages induced by lipopolysaccharide (LPS) stimulation, and supplementation with SO₂ donors or AAT1 overexpression restored SO₂ content, suppressed protein expression of inducible nitric oxide synthase, restrained mRNA level of M1 phenotype-related genes tumor necrosis factor α, interleukin-1β and interleukin-12β and decreased the CD86 expression. In addition, AAT1-knockdowned macrophages exhibited reduced level of hypoxia-inducible factor-1α (HIF-1α) hydroxylation, elevated HIF-1α protein level, and polarization into M1-type, while supplementation with SO₂ reversed the above effects. Mechanistically, SO₂ maintained prolyl hydroxylase (PHD) activity in a thiol-dependent manner. SO₂ maintained PHD2 activity by sulphenylating PHD2 at Cys260, thereby reducing HIF-1α protein levels and subsequently inhibiting M1 macrophage polarization. Besides, SO₂ enhanced PHD2 sulphenylation, inhibited M1 macrophage polarization, and alleviated lung damage in a mouse model of LPS-induced acute lung injury. These results suggested that downregulation of the endogenous SO₂/AAT1 pathway was a pivotal mechanism for M1 macrophage polarization. SO₂ maintained PHD2 activity via sulphenylation of Cys260, and promoted HIF-1α hydroxylation and degradation, thereby impeding M1 macrophage polarization.

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