Hypoxia-inducible factor 1-alpha inhibitor (FIH-1) (FIH-1)

Hypoxia-inducible factor 1-alpha inhibitor (FIH-1), encoded by the HIF1AN gene, is a Fe(II)- and 2-oxoglutarate-dependent asparaginyl hydroxylase that serves as a critical oxygen sensor in mammalian cells (UniProt, 2024). It regulates the transcriptional activity of hypoxia-inducible factors (HIFs) by hydroxylating a specific asparagine residue (Asp803 in HIF-1α) within their C-terminal transactivation domain (CAD). This hydroxylation sterically blocks the interaction between HIF and its transcriptional co-activators, p300 and CBP, effectively silencing the hypoxic gene expression program under normoxic conditions (Lando et al., 2002). Unlike prolyl hydroxylases (PHDs) that target HIF for degradation, FIH-1 has a higher affinity for oxygen, allowing it to function as a fine-tuner of the hypoxic response at intermediate oxygen levels (Hewitson et al., 2002). In clinical research, FIH-1 is a target of interest for treating ischemic diseases, anemia, and metabolic disorders, as its inhibition can enhance the adaptive response to low oxygen (Wilkins et al., 2016). However, therapeutic development faces challenges regarding the selectivity of inhibitors and the potential risk of promoting tumor-supportive pathways like angiogenesis and glycolysis (Zhang et al., 2010).

Other names

HIF1ANFactor inhibiting HIF-1Asparaginyl hydroxylase FIH1Peptide-aspartate (asparagine) dioxygenase

Inhibition of asparaginyl hydroxylase activity to prevent HIF-1α CAD hydroxylation, thereby promoting p300/CBP recruitment and HIF-mediated transcription (Lando et al., 2002; Wilkins et al., 2016).