Hepatocellular carcinoma remains one of the most challenging cancer types to treat due to its limited therapeutic targets.  

In this study, phosphorylated c-Jun N-terminal kinase was introduced as a potential anti-HCC target, and JNK-IN-5A derivatives were evaluated for their therapeutic potential.  

The findings showed that SET135 and SET171 demonstrated strong anti-tumor activity by inducing apoptosis, autophagy, cell-cycle arrest, and necrotic cell death mechanisms. 

Compared with sorafenib and regorafenib, these compounds exhibited enhanced efficacy in vitro, while in vivo results also indicated superior anti-tumor effects compared to sorafenib.

RNA-seq and systems biology analyses further revealed distinct mechanisms of action: SET135 was associated with p62/SQSTM1-mediated autophagic necrosis, whereas SET171 induced ROS-driven necrosis.

These results highlight JNK-IN-5A derivatives as promising therapeutic candidates for hepatocellular carcinoma and point to p-JNK stabilization as a valuable strategy in future anti-cancer drug development.