Targeting MAPK9 in neurodegenerative diseases: mechanistic insights, phytochemical modulators, and emerging computational approaches

The protein Mitogen-activated protein kinase 9 (MAPK9) (c-Jun N-terminal kinase 2 [JNK2]) is a critical signalling molecule involved in cellular survival, inflammation, oxidative stress, and the programming of cell death. This is because there has been emerging evidence of the effects of the abnormal activation of MAPK9 in the pathogenesis and progression of neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, many medicinal plants possess multiple phytoconstituents with neuroprotective activity that can modulate the MAPK9 signalling cascade and protect neurons against injury. Thus, this review focuses on the biology and signalling pathways of MAPK9, its function in neurodegeneration, and medicinal plants and phytochemicals targeting MAPK9, together with their biological mechanism(s) of action. Recent advancements in drug design and discovery, involving computational techniques such as molecular docking, network pharmacology, and artificial intelligence, were also discussed. Additionally, current problems, limitations, and possibilities in the clinical translation of these natural compounds were highlighted. Therefore, knowledge of how these phytochemicals modulate the MAPK9 signalling pathway may offer safer, more effective preventive and therapeutic approaches for neurodegenerative disorders.