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

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.