The Role of Hypoxia-Inducible Factors (HIFs) in Human Diseases

Dear Colleagues,

Hypoxia-inducible factors, or HIFs, are the key transcriptional activators of the cellular response to a lack of oxygen (or hypoxia). As such, they play both positive and negative roles in diseases that cause an unbalance in the availability of oxygen for tissues and/or tissues’ consumption of it. HIFs are thought to be protective and facilitate recovery from disorders such as coronary artery disease, myocardial infarction, peripheral arterial disease, stroke (cerebral ischemia), colitis and, most prominently, anemia. In all these cases, it may be particularly advantageous to devise therapeutic approaches that aim to increase the expression and/or activity of HIFs in affected tissues. Some successful examples of this approach are the several different HIF-prolyl hydroxylase inhibitors (HIF-PHIs) that were recently launched as drugs for oral administration to induce HIF-2 expression and, subsequently, activate endogenous EPO production in order to treat anemia in chronic kidney disease. On the other hand, HIFs are thought to be directly responsible for or contribute to the pathogenicity and progression of disorders such as hereditary erythrocytosis, pulmonary arterial hypertension, non-alcoholic fatty liver disease, ocular neovascularization, and, most significantly, cancer. In these conditions, inhibition of the expression and/or activity of HIFs may be a promising therapeutic strategy. This proposal has been validated by the recent approval and introduction of Belzutifan, a HIF-2α specific  inhibitor, as a new treatment option for patients with Von Hippel–Lindau (VHL)-related renal cell carcinoma (RCC) and sporadic metastatic RCC. It is not hard to imagine that these successfully tested drugs may soon be repurposed for the treatment of other hypoxia-related disorders, along with a whole battery of new HIF-targeting agents that are under development or being tested in clinical trials. The efficacy of these new drugs, however, depends heavily on exhaustive analyses and complete understanding of the often complex and controversial role of HIFs in the pathogenesis of these diseases.

Prof. Dr. Efrosyni Paraskeva
Prof. Dr. George Simos
Guest Editors

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• oxygen
• hypoxia
• HIF
• transcription
• cancer
• anemia
• ischemia
• cardiovascular disorders
• erythrocytosis
• pulmonary hypertension