Studies show that polyphenolics exert their anti-HCC capability through autophagy manipulation, including stimulation of Beclin-1, Atg5, Atg7, Atg9, Atg12, LC3-II, and SQSTM1, as well as manipulation of PI3K/Akt/mTOR, PTEN, P38/PPAR-α, JNK/Bcl-2, ER stress, p62, p53-dependent, TGF-β receptor/Smad signaling, and YAP, to exert their sensitizing effects, implying that they are potential multi-functional agents for treatment of HCC, which is a devastating disease. This evidence concerns the gene TP53 and hepatocellular carcinoma.