[10] The active site, which is contained in the pocket between the β-sheets, chelates iron(II) through histidine and aspartate coordination.

[18] It has been proposed that cosubstrate and iron concentrations poise the HIF hydroxylases to respond to an appropriate "hypoxic window" for a particular cell type or tissue.

[19] Studies have revealed that PHD2 has a KM for dioxygen slightly above its atmospheric concentration, and PHD2 is thought to be the most important sensor of the cell's oxygen status.

[27] HIF's important role as a homeostatic mediator implicates PHD2 as a therapeutic target for a range of disorders regarding angiogenesis, erythropoeisis, and cellular proliferation.

[30] Substrate analog peptides have also been developed to exhibit inhibitory selectivity for PHD2 over factor inhibiting HIF (FIH), for which some other PHD-inhibitors show overlapping specificity.

[31] Gasotransmitters including carbon monoxide[32] and nitric oxide[33][34] are also inhibitors of PHD2 by competing with molecular oxygen for binding at the active site Fe(II) ion.

[35] Ischemia, characterized by reduced blood flow and oxygen supply, can lead to severe tissue damage and dysfunction.

[37][38] Preclinical studies have suggested that inhibition of PHD2 can reduce tissue damage in models of myocardial infarction and cerebral ischemia, providing a foundation for future therapeutic strategies aimed at minimizing the consequences of acute ischemic events.

[39] Ongoing research continues to explore the efficacy and safety of PHD2 inhibitors in various ischemic scenarios, with the potential to extend these findings to clinical applications.