Differentiation therapy: Unlocking phenotypic plasticity of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The current treatment of HCC mainly includes surgery, chemotherapy, and liver transplantation. HCC differentiation therapy aims to restore tumor cells' normal liver characteristics and unlock their phenotypic plasticity. Understanding the molecular and signaling pathways that control HCC differentiation can help identify new targets for inducing differentiation and provide ideas for drug design. Downregulation of liver enriched transcription factors, imbalanced signal pathway, and dysregulated microRNA play essential roles in regulating the differentiation state of HCC. Restoring normal expression levels of these molecules could induce the tumor cells to differentiate into hepatocyte-like cells (HLCs) and suppress the malignant tumor phenotype. The strategies for inducing HLCs from induced pluripotent stem cells, fibroblasts, and other somatic cells provide a reference for the induced differentiation of liver cancer. The differentiation therapy is expected to be a promising and effective treatment for HCC.