Schematic diagram of proposed effects of cyproheptadine on the cell cycle in HCC cells. (A) In HepG2 cells, cyproheptadine treatment causes significant activation of p38 MAPK activity, which subsequently mediates induction of p16INK4A and HBP1. As a target of transcriptional regulation by HBP1, p16INK4A gene expression can be further promoted. Cytosolic p16INK4A may ultimately inhibit the activation of the cyclin-dependent protein kinase Cdk4/6, leading to cell cycle arrest in the G1 phase. (B) In Huh-7 cells, cyproheptadine treatment causes significant activation of p38 MAPK activity, which subsequently mediates the p53-independent induction of p27. At the same time, phosphorylation-activated CHK2 can promote p21 induction in a p53-independent way. The induced p21 and p27 contribute to a reduction in the kinase activity of the CDK2–cyclin E complex, which causes Rb to remain in a hypophosphorylated state, leading to cell cycle arrest at the G1/S transition.