Kanno H, Nakahara K. Regenerative potential of von Hippel-Lindau tumor suppressor protein. World J Biol Chem 2026; 17(3): 119936 [DOI: 10.4331/wjbc.119936]
Corresponding Author of This Article
Hiroshi Kanno, MD, PhD, Academic Fellow, Professor, Department of Neurosurgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. hiroshikannomd@nifty.com
Research Domain of This Article
Cell Biology
Article-Type of This Article
review-article
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World J Biol Chem. Sep 5, 2026; 17(3): 119936 Published online Sep 5, 2026. doi: 10.4331/wjbc.119936
Regenerative potential of von Hippel-Lindau tumor suppressor protein
Hiroshi Kanno, Kimihiro Nakahara
Hiroshi Kanno, Department of Neurosurgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
Hiroshi Kanno, Department of Neurosurgery, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
Kimihiro Nakahara, Department of Neurosurgery, International University of Health and Welfare, Narita 286-0048, Japan
Co-first authors: Hiroshi Kanno and Kimihiro Nakahara.
Author contributions: Kanno K researched, wrote, and integrated the information in the manuscript and figures; Nakahara K researched and integrated the information in the manuscript; both authors have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper.
AI contribution statement: Microsoft Copilot has been partially used. The main content of the manuscript was not entirely generated by the AI. Only the language was polished using AI tools. The AI tools did not participate in the research design or the interpretation of the results. All the images were not completely generated by the AI.
Supported by Ministry of Education, Culture, Sports, Science, and Technology of Japan, No. 32713.
Conflict-of-interest statement: There is no conflict of interest associated with any of the authors who contributed their efforts in this manuscript.
Corresponding author: Hiroshi Kanno, MD, PhD, Academic Fellow, Professor, Department of Neurosurgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. hiroshikannomd@nifty.com
Received: February 11, 2026 Revised: March 11, 2026 Accepted: June 17, 2026 Published online: September 5, 2026 Processing time: 204 Days and 14.1 Hours
Abstract
The von Hippel-Lindau (VHL) protein, traditionally known for oxygen sensing via HIF-1α degradation, is now recognized as a multifunctional regulator of neural stem cell (NSC) fate and central nervous system regeneration. This review examines VHL’s role in lineage specification and its therapeutic potential. Under normoxia, VHL promotes rapid neuronal differentiation by suppressing JAK2/STAT and Notch signaling pathways. This relief of repression activates proneural bHLH factors like Neurogenin2 and Ascl1, leading to the generation of electrophysiologically mature, MAP2-positive neurons. Conversely, hypoxia-induced HIF-1α stabilization biases NSCs toward a glial fate, supporting survival and astrocytic differentiation in the injured environment. Beyond its canonical role, specialized modules expand VHL’s utility: The transferable BC-box motif can independently induce neuronal commitment in various somatic stem cells, while the Daam2-VHL-Nedd4 axis supports oligodendrocyte maturation and remyelination. Translational studies in models of Parkinson’s disease and spinal cord injury demonstrate that VHL-based strategies can achieve significant functional recovery. Understanding the context-dependent dynamics of VHL signaling is crucial for advancing regenerative therapies for neurodegenerative and demyelinating disorders.
Core Tip: The mechanism of action of von Hippel-Lindau (VHL) involved in neuronal differentiation is mediated through the inhibition of downstream signaling pathways, JAK-STAT, and HIF-VEGF pathways. In addition, because VHL promotes nerve regeneration, it is expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.
