HIFs

HIFs, or hypoxia-inducible factors, are a family of transcription factors that mediate the cellular response to low oxygen. They form active heterodimers composed of an oxygen-sensitive alpha subunit (HIF-1α, HIF-2α, HIF-3α) and a common beta subunit (HIF-1β/ARNT).

Under normal oxygen levels, prolyl hydroxylases PHD1-3 and the asparaginyl hydroxylase FIH modify HIF-α, promoting degradation via the VHL ubiquitin ligase, and inhibiting transcriptional activity. In hypoxia, hydroxylation decreases, stabilizing HIF-α, which pairs with ARNT, binds hypoxia response elements, and recruits coactivators such as p300/CBP to drive gene expression.

HIF target genes regulate angiogenesis, erythropoiesis, metabolism, and iron homeostasis. Prominent examples include VEGF, erythropoietin (EPO), glucose transporters (GLUT1), glycolytic enzymes (HK2, LDHA), and the transferrin receptor. The resulting shift promotes angiogenesis and glycolysis to adapt to low oxygen.

HIF-1 and HIF-2 have overlapping but distinct roles. HIF-1α is widely expressed and responds quickly to hypoxia, while HIF-2α has tissue-preferential expression and can drive a somewhat different gene set; HIF-3α may modulate or repress HIF signaling.

Physiologically, HIFs support development, placenta formation, and adaptation to high altitude. In disease, tumor hypoxia activates HIFs, contributing to angiogenesis and metastatic potential. Clinically, HIF pathway modulators are explored: prolyl hydroxylase inhibitors (PHIs) aim to treat anemia (e.g., roxadustat), while HIF inhibitors are studied for cancer therapy.

The HIF discovery and its role in oxygen sensing were elucidated in the 1990s, with key contributions by researchers including Gregg Semenza, William Kaelin, and Peter Ratcliffe; their work earned the Nobel Prize in Physiology or Medicine in 2019.