c-Jun: A master regulator of neuroregeneration and neurodegeneration

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.