Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN)

Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN), also known as Factor Inhibiting HIF-1 (FIH-1), is a member of the 2-oxoglutarate-dependent dioxygenase family that acts as a critical oxygen sensor in human cells [1, 5]. Under normoxic conditions, HIF1AN catalyzes the asparaginyl hydroxylation of the HIF-1alpha subunit, which sterically hinders its interaction with the transcriptional co-activators p300 and CBP, thereby silencing the hypoxic gene expression program [4, 18]. In addition to its primary role in regulating the hypoxia response, HIF1AN also hydroxylates several ankyrin repeat domain-containing proteins, including Notch-1 and I-kappa-B alpha, influencing pathways related to cell differentiation and inflammation [5, 7]. In the context of disease, HIF1AN is often viewed as a tumor suppressor because its activity restrains the pro-angiogenic and pro-survival effects of HIF-1; however, its dysregulation is linked to various malignancies and erythrocytosis [1, 7]. Therapeutic interest in HIF1AN focuses on the development of selective inhibitors to stabilize HIF-1 activity for the treatment of anemia and ischemic conditions, where enhancing tissue oxygenation is beneficial [2, 17]. Conversely, increasing HIF1AN activity or mimetic-based repression of HIF-1 is a strategy explored for anticancer therapy [9, 11]. Current pharmacological agents targeting the HIF pathway are often non-selective or favor the prolyl hydroxylase (PHD) family, making the discovery of FIH-specific modulators a significant challenge in drug development [6, 13].

Other names

Factor inhibiting HIF-1FIH-1FIH1Hypoxia-inducible factor asparaginyl hydroxylaseHypoxia-inducible factor 1 alpha subunit inhibitor

HIF1AN (FIH-1) catalyzes the asparaginyl hydroxylation of the HIF-1alpha protein at the Asn-803 residue using oxygen and 2-oxoglutarate as co-substrates [2, 4]. This modification prevents the recruitment of the p300/CBP co-activator complex to the C-terminal activation domain (CTAD) of HIF-1alpha, thereby suppressing the transcription of hypoxia-responsive genes [18, 19]. Inhibition of HIF1AN allows the assembly of the active transcriptional complex, promoting the expression of adaptive genes such as VEGF and EPO [6, 9].