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Review Open Access

Prolyl hydroxylase domain proteins: Localization, regulation, function and their role in erythropoiesis (Review)

  • Authors:
    • Yan Hou
    • Zhao-Hua Zhang
    • Wen-Qian Li
    • Guo-Xiong Han
    • Kuo Shen
    • You-Bang Xie
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
    Copyright: © Hou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 82
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    Published online on: January 12, 2026
       https://doi.org/10.3892/mmr.2026.13792
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Abstract

The present review provided a comprehensive exploration of the subtypes of prolyl hydroxylase domain (PHD) enzymes, with a focus on their localization, regulatory mechanisms and functional roles. Additionally, the development of pharmacological agents targeting PHDs and their crucial involvement in erythropoiesis were examined. Under hypoxic conditions, cells initiate a cascade of adaptive biological responses, numerous of which are governed by the transcriptional complexes of the hypoxia‑inducible factor (HIF) family. The intricate balance among HIF‑1α, HIF‑2α and HIF‑3α plays a fundamental role in orchestrating the transcription of genes involved in red blood cell production, angiogenesis, vascular homeostasis, metabolic regulation, and cellular proliferation and survival. HIF‑1α is rapidly upregulated in response to acute hypoxia and is particularly associated with erythropoietin production, whereas HIF‑2α predominantly regulates adaptive responses to chronic hypoxia. The hydroxylation of HIF‑α at two conserved prolyl residues by PHD1‑3 enables its recognition by the von Hippel‑Lindau tumor suppressor protein E3 ubiquitin ligase complex, leading to its polyubiquitination and subsequent proteasomal degradation. In humans, three PHD isoenzymes (PHD1‑3) and an asparaginyl hydroxylase known as factor‑inhibiting HIF have been identified, each exhibiting distinct substrate specificity and tissue distribution patterns. By modulating the hydroxylation of HIFs, PHDs serve as critical regulators of HIF activity, exerting influence over intracellular metabolism, reactive oxygen species, iron (Fe) bioavailability, nitric oxide signaling and redox equilibrium. These regulatory functions collectively shape a wide range of biological processes under hypoxic conditions. While HIF/PHD inhibitors have been successfully introduced into clinical practice, the development of HIF/PHD activators or functional restorers has faced considerable technical challenges. To date, no studies have reported the discovery of HIF/PHD activators. Nevertheless, targeting the HIF/PHD axis has already shown clinical value in treating anemia associated with chronic kidney disease, and ongoing research may expand its therapeutic potential to other hypoxia‑related disorders. Advancing research in this domain holds promise for pioneering novel therapeutic strategies, particularly for conditions such as polycythemia and chronic mountain sickness, where breakthroughs remain critically needed.

View Figures

Figure 1

Mechanistic action of the
pVHL/PHD/HIF pathway, the alterations in HIF2α-ARNT dimerization
under hypoxia, and the downstream targets of HIF. HIF,
hypoxia-inducible factor; PHD, prolyl hydroxylase domain; FIH,
factor-inhibiting HIF; ROS, reactive oxygen species; miR,
microRNA.

Figure 2

Hydroxylation regulation of PHDs.
PHD, prolyl hydroxylase domain; FIH, factor-inhibiting HIF.

Figure 3

Role of HIF/PHD axis in diverse
physiological and pathological processes including erythropoiesis
and iron metabolism, metabolism/redox, growth and apoptosis,
angiogenesis and vascular regulation, migration/motility,
transcriptional regulation and extracellular matrix metabolism.
FIH, factor-inhibiting HIF; PHD, prolyl hydroxylase domain; HIF,
hypoxia-inducible factor.
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Copy and paste a formatted citation
Spandidos Publications style
Hou Y, Zhang Z, Li W, Han G, Shen K and Xie Y: <p>Prolyl hydroxylase domain proteins: Localization, regulation, function and their role in erythropoiesis (Review)</p>. Mol Med Rep 33: 82, 2026.
APA
Hou, Y., Zhang, Z., Li, W., Han, G., Shen, K., & Xie, Y. (2026). <p>Prolyl hydroxylase domain proteins: Localization, regulation, function and their role in erythropoiesis (Review)</p>. Molecular Medicine Reports, 33, 82. https://doi.org/10.3892/mmr.2026.13792
MLA
Hou, Y., Zhang, Z., Li, W., Han, G., Shen, K., Xie, Y."<p>Prolyl hydroxylase domain proteins: Localization, regulation, function and their role in erythropoiesis (Review)</p>". Molecular Medicine Reports 33.3 (2026): 82.
Chicago
Hou, Y., Zhang, Z., Li, W., Han, G., Shen, K., Xie, Y."<p>Prolyl hydroxylase domain proteins: Localization, regulation, function and their role in erythropoiesis (Review)</p>". Molecular Medicine Reports 33, no. 3 (2026): 82. https://doi.org/10.3892/mmr.2026.13792
Copy and paste a formatted citation
x
Spandidos Publications style
Hou Y, Zhang Z, Li W, Han G, Shen K and Xie Y: <p>Prolyl hydroxylase domain proteins: Localization, regulation, function and their role in erythropoiesis (Review)</p>. Mol Med Rep 33: 82, 2026.
APA
Hou, Y., Zhang, Z., Li, W., Han, G., Shen, K., & Xie, Y. (2026). <p>Prolyl hydroxylase domain proteins: Localization, regulation, function and their role in erythropoiesis (Review)</p>. Molecular Medicine Reports, 33, 82. https://doi.org/10.3892/mmr.2026.13792
MLA
Hou, Y., Zhang, Z., Li, W., Han, G., Shen, K., Xie, Y."<p>Prolyl hydroxylase domain proteins: Localization, regulation, function and their role in erythropoiesis (Review)</p>". Molecular Medicine Reports 33.3 (2026): 82.
Chicago
Hou, Y., Zhang, Z., Li, W., Han, G., Shen, K., Xie, Y."<p>Prolyl hydroxylase domain proteins: Localization, regulation, function and their role in erythropoiesis (Review)</p>". Molecular Medicine Reports 33, no. 3 (2026): 82. https://doi.org/10.3892/mmr.2026.13792
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