Neuroprotective action of PHD inhibitors is predominantly HIF-1-independent: An Editorial for 'Sex differences in neonatal mouse brain injury after hypoxia-ischemia and adaptaquin treatment' on page 759.

Hypoxia-inducible factor (HIF-1) as the primary factor mediating gene-dependent cellular responses to hypoxia represents an attractive target for the therapeutic interventions. The current Editorial comments on an as yet underestimated facet of HIF-1-related research. The activity of HIF-1 is being regulated by the availability of its α-subunit HIF-1α, which undergoes quick degradation. The process of degradation is initiated by prolyl 4-hydroxylase (PHD). PHD is an oxygen-dependent enzyme and therefore is inactivated in hypoxia, in turn resulting in HIF-1α stabilization, its dimerization with HIF-1β subunit thereby producing the transcriptionally active factor. It has been suggested that pharmacological inhibition of PHD activity might give the same results. Indeed, a large body of evidence on beneficial effects of PHD inhibitors has been accumulated in multiple laboratory and clinical trials. In addition to them, a paper by Li and colleagues published in this issue of Journal of Neurochemistry also reports that inhibition of PHD by adaptaquin reduces hypoxic-ischemic brain injury in a neonatal mouse model. When dissecting the underlying molecular mechanisms, Li and colleagues surprisingly found that the observed effects appear to be independent of HIF-1. These findings draw attention back to the question about possible HIF-1 effects independent of PHD inhibitors, which has been raised several years ago but has not received sufficient attention so far, and is being discussed in this Editorial. One of the possible mechanisms might be ascribed to the ferroptosis pathway affected by PHD inhibitors but this question needs further careful studies, as well as clarification of other mechanisms possibly involved. Even if they represent a prospective therapeutic strategy, the lack of current knowledge about endogenous targets of PHD inhibitors, except for PHD, calls for a careful and balanced approach toward their clinical use.