Hif 2Edit
Hypoxia-inducible factor 2 (HIF-2), encoded by the gene EPAS1, is a central regulator of the cellular response to low oxygen. Along with its sibling HIF-1, HIF-2 coordinates transcriptional programs that adjust metabolism, blood formation, and blood vessel growth when tissues experience hypoxia. HIF-2 functions as a heterodimer composed of an oxygen-sensitive alpha subunit (HIF-2α) and the constitutively expressed partner ARNT (HIF-1β). The stability and activity of HIF-2 are controlled by oxygen-sensing enzymes called prolyl hydroxylases (PHDs) and the von Hippel-Lindau (VHL) protein, which marks stabilized HIF-2 for degradation under normal oxygen levels. This tightly regulated system enables cells to adapt rapidly to changing oxygen availability. In the clinic, HIF-2 has moved from a basic biology topic to a therapeutic target, particularly for tumors driven by dysregulated oxygen sensing.
HIF-2’s biology sits at the intersection of development, physiology, and disease. In normal physiology, HIF-2 influences erythropoiesis (the production of red blood cells) and iron metabolism, and it contributes to angiogenesis and metabolic reprogramming in hypoxic tissues. In cancer, HIF-2 can promote tumor growth and neovascularization in certain contexts, particularly when pathways like VHL are compromised. Because HIF-2 activity reflects cellular oxygen status, tumors that rely on hypoxic signaling can become vulnerable to therapies that block HIF-2–driven transcription. The dual role of HIF-2 in normal adaptation and disease makes it a focal point for both basic science and translational medicine.
Biology and function
Structure and regulation: HIF-2 is a heterodimer of HIF-2α and ARNT. Under normal oxygen, prolyl hydroxylases modify HIF-2α, enabling VHL to target it for degradation. Under low oxygen, stabilization of HIF-2α allows the complex to accumulate, bind DNA at hypoxia response elements, and activate target genes. Key target genes include those involved in erythropoiesis, angiogenesis, and iron handling. See the broader framework of Hypoxia-inducible factors signaling for context.
Tissue distribution and roles: HIF-2 shows preferential activity in certain cell types, such as vascular endothelium and specific renal and pulmonary cells, where it can influence vascular tone, oxygen delivery, and metabolic adaptation. In contrast, HIF-1 tends to dominate some acute hypoxic responses. This division of labor helps explain why HIF-2 and HIF-1 have overlapping but distinct biological effects.
Relationship to other players: The activity of HIF-2 intersects with pathways involving erythropoietin (Erythropoietin), vascular endothelial growth factor (VEGF), and iron metabolism, creating a coordinated response to hypoxia across multiple organ systems.
Genetics and regulation
The EPAS1 gene encodes the HIF-2α subunit. Variants in EPAS1 contribute to differences in high-altitude adaptation in human populations, illustrating how hypoxic signaling can shape physiology over evolutionary time. See EPAS1 for a gene-centered view of its structure and regulation.
Oxygen sensing and degradation: PHD enzymes (including PHD2/EGLN1) hydroxylate HIF-2α in the presence of oxygen, enabling recognition by VHL. When VHL is impaired or when oxygen is scarce, HIF-2α escapes degradation and promotes transcription of hypoxia-responsive genes. The activity of this axis ties together cellular oxygen sensing with systemic responses such as red blood cell production and angiogenesis.
Cross-talk within the HIF family: HIF-2 interacts with HIF-1–regulated programs, but it also has unique targets and tissue effects. Understanding these distinctions is important for predicting responses to HIF-2–targeted therapies and for interpreting how tumors adapt to hypoxic stress.
Clinical significance
Normal physiology and adaptation: HIF-2 signaling helps organisms cope with reduced oxygen availability, including processes like erythropoiesis and maintenance of oxygen delivery to tissues. Variants in hypoxia pathway genes have been linked to differences in high-altitude physiology, illustrating a direct link between hypoxic signaling and systemic adaptation.
Disease implications: In cancers such as clear cell renal cell carcinoma and other tumors where the VHL pathway is disrupted, HIF-2 can drive tumor growth and angiogenesis. The dysregulation of HIF-2 signaling in these contexts has made it a compelling target for therapy and a biomarker of disease activity in some settings.
Therapeutic targeting and drugs: A major milestone is belzutifan (also known as MK-6482), a first-in-class HIF-2α inhibitor. Belzutifan has been approved for patients with von Hippel-Lindau disease–associated renal cell carcinoma, CNS hemangioblastomas, and pancreatic neuroendocrine tumors. By blocking HIF-2α, the drug aims to reduce tumor growth driven by hypoxic signaling. See belzutifan for a more detailed pharmacologic profile and clinical data.
Side effects and considerations: Inhibiting HIF-2α can affect erythropoiesis and iron handling, so anemia and related symptoms are among the anticipated adverse effects. Long-term safety and the broader consequences of sustained HIF-2 inhibition are active areas of clinical observation and study.
Therapeutics and research
Belzutifan and clinical use: Belzutifan represents a targeted approach against a fundamental regulator of the hypoxic response. Its approval marked a shift toward treatments that address the upstream drivers of tumor biology in VHL-related diseases and potentially in other tumors with HIF-2 dependence. Ongoing research explores additional indications, combination therapies, and long-term outcomes.
Other inhibitors and development: Early-stage research has examined other HIF-2α inhibitors, alongside translational work to understand resistance mechanisms and patient selection. The aim is to refine who benefits most from HIF-2–targeted therapy and to identify combinations that improve efficacy while managing toxicity. See PT2385 and related exploration for context, if available in your encyclopedia.
Broader implications: The HIF pathway is a central node in cancer biology, cardio-respiratory physiology, and hematology. Therapeutic strategies that modulate HIF-2 must balance anti-tumor activity with preservation of normal hypoxic responses, to avoid unintended consequences in patients’ oxygen-sensing systems.
History and discovery
The hypoxia-inducible factor family was identified and characterized over the past few decades, with HIF-1 as an early landmark and HIF-2 discovered later as a distinct but related regulator. The understanding of HIF-2’s roles evolved from basic biology to translational medicine as researchers linked its activity to specific tumor phenotypes and patient outcomes.
The emergence of HIF-2 as a drug target culminated in the development and regulatory approval of belzutifan, illustrating a path from molecular understanding to targeted therapy for genetic–syndromic tumors.