Phospho-JNK agonists show promising effects for the treatment of hepatocellular carcinoma
Woonghee Kim, Han Jin, Xinmeng Liao, Mengzhen Li, Mathias Uhlen, Cheng Zhang, Adil Mardinoglu, Peipei Miao, Xiaojing Shi, Mehmet Ozcan, Shazia Iqbal, Jihad Sebhaoui, Sajda Ashraf, Burcu Belmen, Hasan Turkez, Jan Boren
article (Uluslararası, Hakemli) | Yazar(lar): Woonghee Kim, Han Jin, Xinmeng Liao, Mengzhen Li, Mathias Uhlen, Cheng Zhang, Adil Mardinoglu, Peipei Miao, Xiaojing Shi, Mehmet Ozcan, Shazia Iqbal, Jihad Sebhaoui, Sajda Ashraf, Burcu Belmen, Hasan Turkez, Jan Boren | Yıl: 2026 | Dergi/Kurum: ISCIENCE | İndeks: WOS.SCI |
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.