pseudohypoxic

Pseudohypoxic refers to a state in which cells activate hypoxia-inducible factor (HIF)–driven gene expression and downstream hypoxic responses despite normal tissue oxygen levels. The term is commonly used in oncology and metabolism to describe conditions that mimic hypoxic signaling without actual oxygen deprivation.

Mechanism focuses on the HIF pathway. Under normoxic conditions, prolyl hydroxylases (PHDs) hydroxylate HIF-α, marking it for VHL-mediated degradation. When oncometabolites such as succinate, fumarate, or 2-hydroxyglutarate accumulate, they inhibit PHDs and other α-ketoglutarate–dependent dioxygenases. This inhibition stabilizes HIF-α, which dimerizes with HIF-β, enters the nucleus, and drives transcription of glycolytic enzymes, vascular endothelial growth factor (VEGF), and other hypoxia-responsive genes. In addition, oncometabolite-induced epigenetic changes through inhibition of TET enzymes and histone demethylases can reinforce pseudohypoxic signaling.

Causes and contexts include genetic alterations in Krebs cycle enzymes. Mutations in SDH (succinate dehydrogenase) or FH (fumarate hydratase) lead to accumulation of succinate or fumarate, while IDH mutations produce 2-hydroxyglutarate. Pseudohypoxic signaling is observed in tumors such as paragangliomas, pheochromocytomas, renal cell carcinoma, and certain gliomas, and can also arise in non-neoplastic tissues under metabolic stress.

Clinical significance centers on the consequences of HIF target gene activation, which promotes angiogenesis, metabolic reprogramming, and invasive behavior. Therapeutic considerations include strategies to inhibit HIF signaling or address the underlying metabolic disturbances, with research exploring HIF inhibitors and approaches to counteract oncometabolite accumulation.

Pseudohypoxia is distinct from true hypoxia, as it results from metabolic or genetic alterations rather than reduced oxygen tension, though its effects on cellular behavior can be similar.