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JNK activation is regulated in a complex manner by upstream kinases and phosphatases, and plays an important role in physiological processes such as the immune response and neuronal function. Therefore, JNK has become a therapeutic target for neurodegenerative diseases, ankylosing spondylitis, psoriasis, arthritis and other diseases. Inhibition of JNK activation in mitochondria holds great potential for Parkinson's disease (PD) therapy. However, no specific mitochondrial\u2010targeted JNK inhibitor has been reported. We have developed a mitochondrial\u2010targeted JNK inhibitor, <jats:bold>P2<\/jats:bold>, by linking a mitochondrial\u2010specific cell\u2010penetrating peptide to SP600125 (<jats:bold>SP<\/jats:bold>), a commercialized specific inhibitor of JNK. We found that <jats:bold>P2<\/jats:bold> specifically inhibited mitochondrial JNK phosphorylation instead of nuclear JNK signaling. Further studies showed that <jats:bold>P2<\/jats:bold> effectively rescued PD phenotypes both in\u2005vitro and in\u2005vivo, thus indicating that it is a potential therapeutic for PD.<\/jats:p>","DOI":"10.1002\/cbic.202200748","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T05:45:08Z","timestamp":1679463908000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Design and Synthesis of a Mitochondrial\u2010Targeted JNK Inhibitor and Its Protective Effect on Parkinson's Disease Phenotypes"],"prefix":"10.1002","volume":"24","author":[{"given":"Zhiqiang","family":"Zhou","sequence":"first","affiliation":[{"name":"Key Laboratory of Flexible Electronics (KLOFE) &amp; Institute of Advanced Materials (IAM) Nanjing Tech University  5 Xinmofan Road Nanjing 211816 P. R. 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