Phospho-JNK agonists show promising effects for the treatment of hepatocellular carcinoma
iScience, vol.29, no.6, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 29 Issue: 6
- Publication Date: 2026
- Doi Number: 10.1016/j.isci.2026.116005
- Journal Name: iScience
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Directory of Open Access Journals
- Keywords: Biological sciences
- Ataturk University Affiliated: Yes
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.