New Insights in Hypoxic Response Modulation

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 409

Special Issue Editor


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Guest Editor
Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a Street, 50-383 Wroclaw, Poland
Interests: HIF-1; HIF-2; HIF-3; unfolded protein response; IRE1; XBP1
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Special Issue Information

Dear Colleagues,

The imbalance between oxygen availability and demand at both tissue and cellular levels, termed “hypoxia”, triggers a rapid global reprogramming of gene expression to ensure survival and restore oxygen homeostasis. Additionally, since oxygen supply can be quickly restored, the hypoxia response also minimizes the risk of oxidative damage and activates cell death if oxygen levels cannot be restored.

Recent breakthroughs in research and technology have provided better insights into the metabolism of hypoxic cells and have highlighted the complexity of the tumor microenvironment (TME). Moreover, novel molecular mechanisms, including noncoding RNA-related regulatory networks, have introduced new regulatory circuits and therapeutic opportunities for hypoxic response. MicroRNAs, long noncoding RNAs, PiRNA, and other RNA molecules can significantly influence Hypoxia-Inducible Factor (HIF) activity and determine the fate of hypoxic cells. Furthermore, the development of synthetic analogs of these molecules and targeted delivery methods opens new therapeutic avenues that could significantly impact patients’ lives.

The ability to develop therapeutic strategies based on the molecular mechanisms underlying the hypoxic response is crucial for modern treatments of ischemic events, stroke, myocardial infarction, and various human tumors, as well as macular degeneration, glaucoma progression, and diabetic retinopathy. Although HIFs are recognized as master regulators of the hypoxic response, disease-specific therapeutic modulation of their activity remains challenging.

This Special Issue focuses on novel advances in our understanding of the biological and therapeutic roles of molecular mechanisms in regulating cell signaling and fate under hypoxia or ischemia.

Dr. Rafał Bartoszewski
Guest Editor

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Keywords

  • hypoxia
  • oxygen homeostasis
  • oxidative damage
  • cell death
  • ischemic events
  • stroke
  • myocardial infarction
  • tumor microenvironment (TME)
  • noncoding RNA
  • MicroRNAs
  • long noncoding RNAs
  • PiRNA
  • hypoxia-inducible factors (HIFs)
  • targeted delivery
  • hypoxic cells
  • regulatory networks
  • therapeutic opportunities

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Published Papers (1 paper)

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25 pages, 4627 KiB  
Article
Dual Inhibition of HIF-1α and HIF-2α as a Promising Treatment for VHL-Associated Hemangioblastomas: A Pilot Study Using Patient-Derived Primary Cell Cultures
by Ana B. Perona-Moratalla, Blanca Carrión, Karina Villar Gómez de las Heras, Lourdes Arias-Salazar, Blanca Yélamos-Sanz, Tomás Segura and Gemma Serrano-Heras
Biomedicines 2025, 13(5), 1234; https://doi.org/10.3390/biomedicines13051234 - 19 May 2025
Viewed by 268
Abstract
Background: Von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome, is characterized by mutations in the VHL gene, which result in the stabilization of hypoxia-inducible factors (HIF)-1α and -2α, ultimately leading to the development of highly vascularized tumors, such as hemangioblastomas of the central [...] Read more.
Background: Von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome, is characterized by mutations in the VHL gene, which result in the stabilization of hypoxia-inducible factors (HIF)-1α and -2α, ultimately leading to the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system (CNS-HBs). The standard treatment for these brain tumors is neurosurgical resection. However, multiple surgeries are often necessary due to tumor recurrence, which increases the risk of neurological sequelae. Thus, elucidation of the proliferative behavior of hemangioblastomas (with the aim of identifying biomarkers associated with tumor progression) and the development of pharmacological therapies could reduce the need for repeated surgical interventions and provide alternative treatment options for unresectable CNS-HBs. Belzutifan (Welireg™), a selective HIF-2α inhibitor and the only FDA-approved non-surgical option, has shown limited efficacy in CNS-HBs, highlighting the need for alternative therapeutic strategies. Results: In this study, primary cell cultures were successfully established from CNS-HB tissue samples of VHL patients, achieving a 75% success rate. These cultures were predominantly composed of stromal cells and pericytes. The proliferative patterns of patient-derived HB cell cultures significantly correlated with tumor burden and recurrence in VHL patients. Furthermore, flow cytometry, reverse transcription-PCR, and Western blot analyses revealed marked overexpression of both HIF-1α and HIF-2α isoforms in primary HB cells. In addition, evaluation of the therapeutic potential of acriflavine, a dual HIF-1α/HIF-2α inhibitor, demonstrated reduced HB cells viability, induced G2/M cell cycle arrest, and predominantly triggered necrotic cell death in patient-derived HB cultures. Conclusions: These results suggest that the in vitro proliferative dynamics of HB cell cultures may reflect clinical characteristics associated with CNS-HB progression, potentially serving as indicators to predict tumor development in patients with VHL. Furthermore, our findings support the simultaneous targeting of both HIF-1α and HIF-2α isoforms as a promising non-invasive therapeutic strategy. Full article
(This article belongs to the Special Issue New Insights in Hypoxic Response Modulation)
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