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Hypoxic responses are mainly regulated by heterodimeric transcription factor HIF, composed of unstable α-subunit (HIFα) and stable β-subunit (HIF1β/ARNT). Protein stability of HIFα depends on the hydroxylation status of its specific proline residue(s). Prolyl hydroxylation of HIFα is regulated by iron- and 2-oxoglutarate (2-OG)-dependent dioxygenase PHDs, whose enzyme activities are oxygen-dependent. Hence, PHDs act as an oxygen sensor, and inhibiting PHDs can activate the hypoxic response regardless of the normoxic environment. Small compounds that inhibit PHDs have been developed as the therapeutics for renal anemia. Here we also introduce the medical application of the PHD-inhibitors other than the renal anemia treatment. Finally, it is a great pleasure to announce here that the Nobel Prize in Physiology or Medicine 2019 was awarded to William G. Kaelin Jr, Sir Peter J. Ratcliffe, and Gregg L. Semenza, who have been studying how cells sense and adapt to oxygen availability over the years.

Hypoxic response as a therapeutic target of human diseases