Factor inhibiting hypoxia-inducible factor 1 (FIH-1) (FIH-1)

Factor inhibiting hypoxia-inducible factor 1 (FIH-1) is a 2-oxoglutarate-dependent dioxygenase that acts as a key negative regulator of the hypoxia-inducible factor (HIF) transcriptional complex (UniProt: Q9NWT6) [1]. It functions by hydroxylating a specific asparagine residue (Asn-803 in human HIF-1α) within the C-terminal transactivation domain of HIF-alpha subunits (PubMed: 11836526) [2]. This modification prevents the recruitment of the p300/CBP co-activators, thereby suppressing the transcriptional activity of HIF under normoxic conditions (Wikipedia: Factor inhibiting HIF) [3]. While prolyl hydroxylases (PHDs) primarily regulate HIF stability through degradation, FIH serves as a secondary mechanism to fine-tune the activity of the HIF protein that escapes degradation (PubMed: 25611106) [4]. Pharmacological inhibition of FIH is being explored for treating conditions like anemia, ischemic diseases, and metabolic disorders by enhancing the adaptive response to low oxygen (Nature Reviews Molecular Cell Biology) [5]. However, therapeutic targeting of FIH presents challenges, as sustained HIF activation may promote angiogenesis and survival in tumor cells, potentially facilitating cancer progression (PubMed: 12150925) [6].

Other names

HIF1ANHypoxia-inducible factor 1-alpha inhibitorFIH1Peptide-asparagine dioxygenaseAsparaginyl hydroxylase FIH

Inhibition of the asparaginyl hydroxylase activity of FIH prevents the hydroxylation of the C-terminal transactivation domain (CAD) of HIF-alpha subunits. This lack of hydroxylation allows for the recruitment of p300/CBP co-activators to the HIF complex, thereby increasing the transcription of hypoxia-responsive genes such as EPO and VEGF (PubMed: 11836526) [2].