Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN) (HIF1AN)

Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN), commonly known as Factor Inhibiting HIF-1 (FIH-1), is a 2-oxoglutarate-dependent dioxygenase that acts as a key negative regulator of the hypoxia-inducible factor (HIF) signaling pathway [1, 2]. It functions as an asparaginyl hydroxylase, specifically hydroxylating the Asn-803 residue within the C-terminal transactivation domain of HIF-1α under normoxic conditions [2, 3]. This modification prevents the interaction between HIF-1α and essential transcriptional co-activators like p300 and CBP, effectively silencing the expression of genes involved in angiogenesis, glycolysis, and erythropoiesis [3, 4]. In disease states such as cancer, HIF1AN activity influences the metabolic adaptation of tumors, while its inhibition is explored as a strategy to treat ischemic conditions by boosting the body's adaptive response to low oxygen [1, 4]. While the protein is the primary functional target, therapeutic approaches can also target the HIF1AN mRNA using antisense oligonucleotides or siRNA to reduce protein expression and enhance HIF activity. Current pharmacological research focuses on small molecule inhibitors that compete with 2-oxoglutarate to block the enzyme's catalytic site [2].

Other names

FIH1Factor inhibiting HIF-1FIH-1Peptide-asparagine dioxygenaseHypoxia-inducible factor 1 alpha inhibitor

Inhibition of the asparaginyl hydroxylase activity of HIF1AN prevents the hydroxylation of the C-terminal transactivation domain (CTAD) of HIF-1α. This lack of hydroxylation allows HIF-1α to recruit transcriptional co-activators such as p300 and CBP, thereby enhancing the expression of hypoxia-inducible genes even under normoxic or near-normoxic conditions.