Novel senescence inducer ICA-11c, a derivative of icaritin, YAP-dependently suppresses hepatocellular carcinoma cells.

The Hippo/YAP signaling pathway has been implicated in promoting cancer development in liver cancer. YAP serves as its core effector to promote the expression of downstream oncogenes, exacerbating the difficulty in treatment and prognosis. ICA-11c, a derivative of icaritin (ICT), which was designed and synthesized in our previous study, inhibited the proliferation of HepG2 and Huh-7 cells in a concentration-dependent manner. Moreover, ICA-11c promoted G0/G1 cell cycle arrest and cellular senescence by regulating the p53/p21 and p16/RB pathways. Mechanistically, the cellular thermal shift assay (CETSA) and molecular docking assay confirmed the combination between ICA-11c and YAP, which inhibited YAP nuclear translocation, eventually promoted its phosphorylation and reduction in the cytoplasm. Particularly, YAP overexpression attenuated the effect of ICA-11c on cellular senescence as well as its anti-proliferative activity. Our findings not only show that ICA-11c served as a potential YAP regulator for the treatment of hepatocellular carcinoma, but also explore the relationship between YAP and cellular senescence. This study suggests that ICA-11c may be a potential novel inducer of cellular senescence in hepatocellular carcinoma cells.