- Hypoxia-Inducible Factor-1 (HIF-1) is a transcription factor that plays a central role in cellular adaptation to low oxygen conditions (hypoxia).
- It functions as a master regulator of oxygen homeostasis by activating the transcription of a wide range of genes that enable cells and tissues to survive and adapt when oxygen supply is limited. These genes are involved in processes such as angiogenesis, erythropoiesis, glucose metabolism, and cell survival. Through this regulation, HIF-1 coordinates the physiological response to hypoxia in both normal and pathological contexts.
- HIF-1 is a heterodimeric protein composed of two subunits: HIF-1α and HIF-1β (also known as ARNT, the aryl hydrocarbon receptor nuclear translocator). The HIF-1β subunit is constitutively expressed and stable, while HIF-1α is oxygen-sensitive and tightly regulated. Under normal oxygen conditions (normoxia), HIF-1α is hydroxylated by a family of oxygen-dependent enzymes called prolyl hydroxylase domain proteins (PHDs). This hydroxylation marks HIF-1α for recognition by the von Hippel–Lindau (VHL) protein, which targets it for ubiquitination and proteasomal degradation. As a result, HIF-1 activity is low under normoxia.
- In contrast, under hypoxic conditions, the activity of PHDs is suppressed due to the lack of oxygen, which is a required cofactor for hydroxylation. This prevents HIF-1α degradation, allowing it to accumulate in the cytoplasm. The stabilized HIF-1α then translocates into the nucleus, where it dimerizes with HIF-1β. The HIF-1α/β complex binds to specific DNA sequences known as hypoxia-response elements (HREs) in the promoters of target genes, activating their transcription. This gene expression program includes key factors such as VEGF (vascular endothelial growth factor), erythropoietin (EPO), glucose transporters (GLUT1, GLUT3), and various glycolytic enzymes, all of which promote adaptation to low oxygen availability.
- Physiologically, HIF-1 plays a vital role in embryonic development, wound healing, and adaptation to high altitudes, where oxygen availability is limited. It ensures that tissues can increase oxygen delivery (through angiogenesis and erythropoiesis) and optimize energy production (by switching to glycolysis). However, in pathological conditions, HIF-1 activity can be detrimental. In cancer, HIF-1 is often upregulated due to tumor hypoxia, leading to increased VEGF production and angiogenesis, which support tumor growth and metastasis. HIF-1 also promotes metabolic reprogramming of cancer cells toward glycolysis (the “Warburg effect”), enhancing their survival in hypoxic microenvironments. Beyond cancer, HIF-1 has been implicated in ischemic diseases, chronic lung disease, pulmonary hypertension, and inflammatory disorders, where its activity contributes to disease progression.
- Clinically, HIF-1 is an attractive therapeutic target. In oncology, strategies to inhibit HIF-1 activity are being explored to suppress tumor angiogenesis and metabolic adaptation. Conversely, in conditions like anemia, ischemic heart disease, and stroke, controlled activation of HIF-1 could be beneficial by stimulating erythropoiesis and angiogenesis to improve oxygen supply. Drugs that modulate HIF pathways, such as PHD inhibitors (e.g., roxadustat), are already in use for the treatment of anemia in chronic kidney disease, where they work by stabilizing HIF-1α and enhancing endogenous erythropoietin production.
