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Biomedicines
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New Insights in Hypoxic Response Modulation
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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 March 2026 | Viewed by 3168

Special Issue Editor

Dr. Rafał Bartoszewski

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals

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

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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 (2 papers)

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25 pages, 4627 KB  
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
Cited by 1 | Viewed by 2445
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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26 pages, 4227 KB  
Systematic Review
Hypoxia-Induced Extracellular Vesicles and Non-Coding RNAs in Cancer: A Systematic Review of Tumor Dynamics and Therapeutic Implications in Preclinical Animal Models
by Joao Pedro R. Afonso, Simona Taverna, Annalisa Pinsino, Giuseppe Cammarata, Rodrigo A. C. Andraus, Iranse O. Silva, Carlos H. M. Silva, Claudia S. Oliveira, Rodrigo F. Oliveira, Deise A. A. P. Oliveira, Orlando A. Guedes, Luciana P. Maia, Wilson R. Freitas Junior, Elias J. Ilias, Juan J. Uriarte, Giuseppe Insalaco and Luis V. F. Oliveira
Biomedicines 2025, 13(11), 2796; https://doi.org/10.3390/biomedicines13112796 - 17 Nov 2025
Viewed by 402
Abstract
Background: Cancer is a heterogeneous pathology, and among causative factors, gene expression can influence its development. Molecular approaches using extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) offer great value in understanding tumor progression, early diagnosis, and potential therapies. Objectives: This systematic review was [...] Read more.
Background: Cancer is a heterogeneous pathology, and among causative factors, gene expression can influence its development. Molecular approaches using extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) offer great value in understanding tumor progression, early diagnosis, and potential therapies. Objectives: This systematic review was conducted in accordance with the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses guidelines. Its main objective was to evaluate the effects of cellular hypoxia in different types of cancer, exclusively using animal models and highlighting the regulatory role of microRNAs and circular RNAs in tumor development. Methods: A literature review was performed using the PubMed/Medline and Scopus databases without year limitations. The initial search yielded 171 articles. After applying the inclusion and exclusion criteria, 25 studies were included in this review. Data analysis showed that animal models provide detailed insights into different types of cancers under hypoxic conditions. Results: Our analysis identified that specific circRNAs, such as circPFKFB4 in breast cancer and circPDK1 in pancreatic cancer, are consistently associated with a worse prognosis and therapeutic resistance. Similarly, miRNAs such as miR-1287-5p (breast cancer) and miR-133a (colorectal cancer) have frequently been identified as tumor suppressors whose levels are altered by hypoxic conditions. Furthermore, the results suggested that in some cancers, the release of EVs may facilitate tumor progression and metastasis. However, manipulation of ncRNA expression causes significant changes in the tumor response, which suggests a therapeutic response. Conclusions: This study shows that the use of animal models is essential for exploring the molecular mechanisms of cancer and establishing new therapeutic approaches. Full article
(This article belongs to the Special Issue New Insights in Hypoxic Response Modulation)
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