The c-Jun-NH(2)-terminal kinase (JNK) signaling pathway plays a critical role in regulating cell fate, being implicated in a multitude of diseases ranging from cancer to neurological and immunological/inflammatory conditions. Not surprisingly, therefore, it has been sought after for therapeutic intervention, and its inhibition has been shown to ameliorate many pathological conditions in experimental systems, paving the way for initial clinical trials. However, the fundamental problem in fully harnessing the potential provided by the JNK pathway has been the lack of specificity, due to the multiple JNK forms that are involved in multiple cellular processes in various cell types. Moreover, lack of sufficient knowledge of all JNK-interacting proteins and substrates has also hindered progress. This review will therefore focus on the role of the JNKs in human diseases and appraise the efforts to inhibit JNK signaling to ameliorate disease conditions, assessing potential challenges and providing insights into possible future directions to efficiently target this pathway for therapeutic use.
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