Collectively, our results suggest that JIB-04-mediated targeting of histone demethylases, such as KDM4B, KDM4D, and KDM6B, inhibits the malignancy of hepatocellular carcinoma via growth inhibition and cell cycle arrest and, in addition, affects the maintenance and viability of liver CSCs. This evidence concerns the gene KDM4B and hepatocellular carcinoma.