Pharmacological and non-pharmacological strategies targeting HIF signaling and hypoxia tolerance: opportunities and limitations for personalized interventions

For acute mountain sickness prevention and the treatment of respiratory, cardiovascular, and nervous system diseases, pharmacological (prolyl hydroxylase domain inhibitors, plant extracts, erythrocyte pyruvate kinase activators, and hemoglobin oxygen affinity allosteric activators) and non-pharmacological approaches (hypoxic training and hypoxic therapy) are used. However, drug use is limited by their toxicity, low bioavailability, and prolonged hypoxia-inducible factor – HIF – activation risks, which may lead to tumor growth initiation, as well as cardiovascular and metabolic disorders. At the same time, the effectiveness of hypoxic exposure varies and depends on the regimen, sex, age, and initial organism tolerance. Among athletes, the live high–train low strategy is the most commonly used, whereas for healthy volunteers and individuals in extreme professions, regimen selection based on a preliminary determination of the organism’s hypoxia tolerance is required. Moderate hypoxic exposure may improve clinical outcomes in patients with cardiovascular and neurological diseases; however, variability in effects is associated with the absence of initial consideration of organism oxygen deficiency tolerance in studies. It determines the effectiveness of hypoxia adaptation and is influenced by genetic, epigenetic, and phenotypic factors, with HIF activation being the most significant. In this review, HIF induction and hypoxic exposure are considered approaches to increase organismal hypoxia tolerance, and the need for a personalized approach, considering them in interventions on healthy individuals and patients, is substantiated.