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Peer-reviewedCC BY-NC-ND 4.0Molecular Medicine Reports

A false sense of hypoxia: Pro-tumorigenic VHL-HIF2α dysregulation in clear cell renal cell carcinoma (Review)

  • Nur Qurratu' Athirah A Rahman1
  • Ahmad Suhail Khazali2
  • Mohamad Aiman Mohtar1
  • Saiful Effendi Syafruddin1
  1. 1UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia
  2. 2Faculty of Applied Sciences, Universiti Teknologi MARA Cawangan Perlis, Kampus Arau, Arau, Perlis 02600, Malaysia
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Abstract

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma and is characterized by bi-allelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. Loss of VHL leads to stabilization of hypoxia-inducible factor α (HIFα), creating a persistent pseudohypoxic or ‘false sense of hypoxia’ state in which HIF signalling remains active despite adequate oxygen tension. Within this context, HIF2α functions as the dominant oncogenic isoform and drives angiogenesis, metabolic rewiring, tumor microenvironment remodeling and modulation of immune responses. In parallel, epigenetic reprogramming and super-enhancer-driven transcriptional programs reinforce ccRCC growth and progression. In this review, these molecular and epigenetic mechanisms were integrated around the VHL-HIF2α pseudohypoxia framework with particular emphasis on pathological angiogenesis, metabolic reprogramming, tumor heterogeneity and super-enhancer biology. Furthermore, current therapeutic strategies, including VEGF/VEGFR-targeted agents, HIF2α inhibitors, mTOR pathway inhibitors and immune checkpoint blockade, were presented, together with mechanisms that limit response durability. Finally, emerging precision-oncology approaches aimed at resolving intratumor heterogeneity, identifying predictive biomarkers and exploiting tumor- and microenvironment-specific vulnerabilities to overcome therapeutic resistance were discussed.

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Cite

BibTeXRIS
BibTeX
@article{rahman2026false,
  title = {{A false sense of hypoxia: Pro-tumorigenic VHL-HIF2α dysregulation in clear cell renal cell carcinoma (Review)}},
  author = {Nur Qurratu' Athirah A Rahman and Ahmad Suhail Khazali and Mohamad Aiman Mohtar and Saiful Effendi Syafruddin},
  journal = {Molecular Medicine Reports},
  year = {2026},
  month = oct,
  doi = {10.3892/mmr.2026.14053},
  url = {https://doi.org/10.3892/mmr.2026.14053},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - A false sense of hypoxia: Pro-tumorigenic VHL-HIF2α dysregulation in clear cell renal cell carcinoma (Review)
AU  - Nur Qurratu' Athirah A Rahman
AU  - Ahmad Suhail Khazali
AU  - Mohamad Aiman Mohtar
AU  - Saiful Effendi Syafruddin
PY  - 2026
DA  - 2026/10/23
JO  - Molecular Medicine Reports
DO  - 10.3892/mmr.2026.14053
UR  - https://doi.org/10.3892/mmr.2026.14053
AB  - Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma and is characterized by bi-allelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. Loss of VHL leads to stabilization of hypoxia-inducible factor α (HIFα), creating a persistent pseudohypoxic or ‘false sense of hypoxia’ state in which HIF signalling remains active despite adequate oxygen tension. Within this context, HIF2α functions as the dominant oncogenic isoform and drives angiogenesis, metabolic rewiring, tumor microenvironment remodeling and modulation of immune responses. In parallel, epigenetic reprogramming and super-enhancer-driven transcriptional programs reinforce ccRCC growth and progression. In this review, these molecular and epigenetic mechanisms were integrated around the VHL-HIF2α pseudohypoxia framework with particular emphasis on pathological angiogenesis, metabolic reprogramming, tumor heterogeneity and super-enhancer biology. Furthermore, current therapeutic strategies, including VEGF/VEGFR-targeted agents, HIF2α inhibitors, mTOR pathway inhibitors and immune checkpoint blockade, were presented, together with mechanisms that limit response durability. Finally, emerging precision-oncology approaches aimed at resolving intratumor heterogeneity, identifying predictive biomarkers and exploiting tumor- and microenvironment-specific vulnerabilities to overcome therapeutic resistance were discussed.
SN  - 1791-2997
SN  - 1791-3004
ER  -