Yan et al. (2018) have reported that CXXC5 antagonizes HCC development by promoting TGF-β induced cell cycle arrest of liver cancer cells. On the contrary, Tan et al. (2018) have shown the CXXC5 promotes HCC malignancies by stimulating the proliferation, migration, and invasion of liver cancer cells. It remains to be determined whether and, if so, how CXXC5 may regulate the trans-differentiation of HSCs during liver fibrosis. Of note, Lee S.H. et al. (2015) have demonstrated that CXXC5-null mice display accelerated subcutaneous wound healing. Here, CXXC5 is linked to hepatocellular carcinoma.