Phospho-JNK agonists show promising effects for the treatment of hepatocellular carcinoma

  • iScience. 2026 May 20;29(6):116005. doi: 10.1016/j.isci.2026.116005.
Woonghee Kim  1 ,  Han Jin  1  2 ,  Peipei Miao  3 ,  Mehmet Ozcan  4 ,  Xinmeng Liao  1 ,  Mengzhen Li  1 ,  Shazia Iqbal  5 ,  Jihad Sebhaoui  5  6 ,  Sajda Ashraf  5 ,  Burcu Belmen  5 ,  Hasan Turkez  7 ,  Jan Boren  8 ,  Mathias Uhlen  1 ,  Xiaojing Shi  3 ,  Cheng Zhang  1  9 ,  Adil Mardinoglu  1  10
Affiliations
  • 1. Science for Life Laboratory, KTH - Royal Institute of Technology, 17165 Stockholm, Sweden.
  • 2. Central Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
  • 3. Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Laboratory Animal Center, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, P.R. China.
  • 4. Faculty of Medicine, Zonguldak Bulent Ecevit University, Zonguldak 67600, Turkiye.
  • 5. Trustlife Labs Drug Research & Development Center, Istanbul 34774, Turkiye.
  • 6. Life and Health Sciences Laboratory, FMP, Abdelmalek Essaadi University, Tetouan 93000, Morocco.
  • 7. Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25030, Turkey.
  • 8. Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, 41390 Gothenburg, Sweden.
  • 9. Institute of Liver Studies, Faculty of Life Science & Medicine, King's College London, London SE5 9RS, UK.
  • 10. Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK.
PMID: 42211113 DOI: 10.1016/j.isci.2026.116005
Abstract

Hepatocellular carcinoma (HCC) remains difficult to treat due to its limited targets. Hence, we introduced phosphorylated c-Jun N-terminal kinase (p-JNK) as an anti-HCC target protein and investigated JNK-IN-5A and six derivatives (SET135, SET156, SET158, SET159, SET171, and SET172) which stabilize p-JNK. In vitro, these compounds outperformed sorafenib and regorafenib, inducing stronger p53-mediated cell-cycle arrest, Autophagy, Apoptosis, and reduced invasiveness via JNK/c-Jun pathways. RNA-seq profiling revealed distinct mechanisms: SET135 triggered autophagic necrosis via p62/SQSTM1, while SET171 induced Reactive Oxygen Species (ROS)-driven necrosis. Systems biology analysis confirmed their enhanced efficacy. A 7-day GLP-like rat toxicity study showed SET135 and SET171 were well-tolerated. In vivo study performed with 21-day treatment of SET135 or SET171 showed superior anti-tumor effects compared to sorafenib via apoptotic mechanisms in HCC-transplanted mice. These findings highlight JNK-IN-5A derivatives as promising HCC therapeutic candidates capable of inducing both apoptotic and necrotic cell death.

Keywords
Biological sciences.
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