The present study evaluated the synergistic efficacy of using licochalcone B (LCB) and fullerene C60 (FnC60) nanoparticles against diethylnitrosamine (DEN)-induced hepatocarcinoma in rats and relevant signaling pathways, with APE1/Ref-1 and CDK-4, as novel anti-cancer- targeting. Here, CDK4 is linked to cancer.