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REVIEW ARTICLE

c-Jun: A master regulator of neuroregeneration and neurodegeneration

Jingjing Huang1,2 ,  Shuo Zhang1 ,  Shaoping Ji1,3 ,  Yunyun Wang1*
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1 Department of Anatomy and Embryology, Henan Provincial Engineering Centre for Tumor Molecular Medicine, School of Basic Medical Science, Henan University, Kaifeng, Henan, China
2 Physical Culture Institute, Tian Fu College of Southwestern University of Finance and Economics, Mianyang, Sichuan, China
3 Center for Molecular Medicine, Zhengzhou Health College, Zhengzhou, Henan, China
GPD, 025130027 https://doi.org/10.36922/GPD025130027
Received: 27 March 2025 | Revised: 11 December 2025 | Accepted: 12 December 2025 | Published online: 8 January 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

As a central component of activator protein 1 transcription factors, c-Jun operates through homo- or heterodimerization with the Jun/Fos family members to regulate gene expression. It exhibits dynamic regulation across development, adult homeostasis, and neural injury, establishing c-Jun as a pivotal modulator of diverse neuronal processes. Mounting evidence highlights c-Jun’s dual role in neuroprotection and neurodegeneration, influencing neuronal apoptosis, survival, axonal transport, and synaptic plasticity processes closely associated with cognitive decline in neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Functional studies using genetic ablation or pharmacological inhibition of c-Jun signaling reveal its biphasic nature: sustained c-Jun activation drives neurodegeneration by inducing pro-apoptotic genes, whereas transient activation promotes neuroregeneration, including axonal sprouting and synaptic remodeling. Phosphorylation of c-Jun at serine 63/73, mediated by its upstream regulator c-Jun N-terminal kinase (JNK), is a key post-translational modification controlling its transcriptional activity. The JNK–c-Jun axis acts as a molecular switch, integrating stress signals to dictate neuronal fate. In neurodegenerative contexts, pathway hyperactivation leads to pathological outcomes. In contrast, in peripheral nerve injury models, precisely timed c-Jun activation triggers regenerative gene programs that are critical for axonal regrowth. These opposing effects emphasize the need for spatiotemporal precision in therapeutically targeting this pathway. This review integrates findings from genetic, molecular, and pharmacological studies to clarify the dual contributions of c-Jun to neuroregenerative and neurodegenerative processes. Emerging therapeutic strategies, such as isoform-selective JNK inhibitors, hold promise for harnessing the potential of c-Jun. A deeper understanding of the role of c-Juns could significantly enhance the efficacy of pharmacological interventions to improve neurological outcomes in neurodegenerative diseases.

Keywords
c-Jun
Activator protein 1
Neuronal apoptosis
Neuroregeneration
Neurogenesis
Neurodegenerative diseases
Funding
This work was supported by grants from the National Natural Science Foundation of China (NSFC) (No. 32200804), the Foundation of Henan Educational Committee (No. 23A310016), the Program for Science and Technology Development in Henan Province (No. 242102311048), and a scientific program for postdoctoral in Henan Province (No. HN2024002).
Conflict of interest
The authors declare that they have no competing interests.
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Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing
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